TW200914452A - Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators - Google Patents

Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators Download PDF

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TW200914452A
TW200914452A TW097122339A TW97122339A TW200914452A TW 200914452 A TW200914452 A TW 200914452A TW 097122339 A TW097122339 A TW 097122339A TW 97122339 A TW97122339 A TW 97122339A TW 200914452 A TW200914452 A TW 200914452A
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compound
alkyl
formula
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chr6
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TW097122339A
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Jean-Michel Vernier
Samedy Ouk
La Rosa Martha Alicia De
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Valeant Pharmaceuticals Int
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

This invention provides potassium channel modulators which are compounds of formula I where at least one of W and Z is N; where the moiety is one of Groups A or B below where Ar is a 1, 2-fused, six membered ring aromatic group, bearing substituents R1 and R2 as defined below, and containing zero or one ring nitrogen atom; and where other substituents are defined herein. The invention also provides a composition comprising a pharmaceutically acceptable carrier and at least one of the following: (i) a pharmaceutically effective amount of a compound of formula I and (ii) a pharmaceutically acceptable salt, ester, or prodrug thereof. The invention also provides a method of preventing or treating a disease or disorder which is affected by activities of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt, ester, or prodrug thereof.

Description

200914452 九、發明說明： 【發明所屬之技術領域】 本發明係關於會調節鉀通道之新穎化合物。此化合物可 用於治療與預防受鉀離子通道活性所影響之疾病與病症。 一種此類症狀為發作病症。 本申請案係依美國專利法§ 119⑷第35條請求關於2007年 6月13曰提出申請之美國臨時申請案號60/934,396之優先權， 其係以全文併於本文供參考。 【先前技術】 已發現瑞提加賓（retigabine) (N-[2-胺基-4-(4-氟基苄胺基）苯 基]胺甲基酸乙酯](美國專利案號5,384,330)為在兒童中發作 病症之一種有效治療藥物。Bialer, M.等人，癬#砰龙1999, 34, 1-41。亦已發現瑞提加賓可用於治療疼痛，包括神經病原 性疼痛。Blackburn-Munro 與 Jensen，五狀P/zamaco/. 2003, 460, 109-116。 一種被稱為”良性家族性新生兒搐搦”之癲癇形式係與 KCNQ2/3通道中之突變有關聯。Biervert，C.等人，Sc/ewce 1998, 27, 403-06 ; Singh, N_A_ 等人，愚，·1998, 18, 25-29 ; Charlier, C. 等人，Ato. Ge㈣· 1998, 18, 53-55 ’ Rogawski，#.經科學 之廣勢 2000, 23, 393-398。後續研究已確立瑞提加賓作用之主要位置 為 KCNQ2/3 通道。Wickenden，A_D.等人，M?/_ P/zarwaco/. 2000, 58, 591-600 ; Main, M.J.等人，Mo/. /Vzarmco/· 2000, 58, 253-62。瑞提加 賓已被証實會在靜息膜電位下增加通道之傳導，且會結合 KCNQ2/3 通道之活化作用閘門。Wuttke，T.V·等人，Mo/. P/zflrmaco/. 132252 200914452 2005, 67, 1009-1017。 認定瑞提加賓作為鉀通道調節劑已促進在與瑞提加賓有 關聯化合物中搜尋其他舒通道調節劑。數項此種搜尋已被 報告於專利文獻中，最特別是下列：WO 2004/058739 ; WO 2004/80950 ; WO 2004/82677 ; WO 2004/96767 ; WO 2005/087754 ;及 W02006/029623。 【發明内容】 於一項具體實施例中，本發明係提供式I化合物200914452 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds that modulate potassium channels. This compound is useful for the treatment and prevention of diseases and conditions which are affected by the activity of potassium ion channels. One such symptom is a seizure disorder. This application claims priority to U.S. Provisional Application Serial No. 60/934,396, filed on Jun. No. s. [Prior Art] Retiigabine (N-[2-amino-4-(4-fluorobenzylamino)phenyl]amine methyl acid ethyl ester] has been found (U.S. Patent No. 5,384,330) It is an effective treatment for episodes in children. Bialer, M. et al., 癣#砰龙1999, 34, 1-41. It has also been found that ritigabine can be used to treat pain, including neuropathic pain. Blackburn - Munro and Jensen, V. P/zamaco/. 2003, 460, 109-116. A form of epilepsy known as "benign familial neonatal sputum" is associated with mutations in the KCNQ2/3 channel. Biervert, C Et al., Sc/ewce 1998, 27, 403-06; Singh, N_A_ et al., Yu, 1998, 18, 25-29; Charlier, C. et al., Ato. Ge (4) · 1998, 18, 53-55 ' Rogawski, #. Science Broad 2000, 23, 393-398. Subsequent studies have established that the main position of the Ritti's role is KCNQ2/3. Wickenden, A_D. et al., M?/_ P/zarwaco /, 2000, 58, 591-600 ; Main, MJ et al., Mo/. /Vzarmco/. 2000, 58, 253-62. Retistatin has been shown to increase channel conduction at resting membrane potential, And will combine KCNQ2/3 The activation of the channel. Wuttke, TV· et al., Mo/. P/zflrmaco/. 132252 200914452 2005, 67, 1009-1017. It is believed that ritigatin as a potassium channel regulator has been promoted in the Search for other Shu channel modulators in related compounds. Several such searches have been reported in the patent literature, most particularly the following: WO 2004/058739; WO 2004/80950; WO 2004/82677; WO 2004/96767; WO 2005 /087754; and W02006/029623. SUMMARY OF THE INVENTION In one embodiment, the present invention provides a compound of formula I

其中W與Z之至少一個為N; 其中後文以”胺環”所表示之部份基團Wherein at least one of W and Z is N; wherein a part of the group represented by an "amine ring" is hereinafter

為下文基團A或B之一Is one of the following groups A or B

，其中Ar為1,2-稠合六員環芳族基團，帶有Where Ar is a 1,2-fused six-membered ring aromatic group with

如下文定義之取代基&與R2，且含有零或一個環氮原子； B 132252 200914452a substituent as defined below with R2 and containing zero or one ring nitrogen atom; B 132252 200914452

，其中Ar為1，2-稠合六員環芳族基團，帶有如下 文定義之取代基心與112，且含有零或一個環氮原子； 其中R]與R2係獨立為Η、CN、鹵素、CH2CN、OH、N02、 ch2f、chf2、cf3、cf2cf3、Cl_C6烷基、c(=0)Ci_C6烷基、 NH-C〗-C6 烷基、NHCtCOC! -C6 烷基、C(=〇)n(CH3 )2、C(=〇)N(Et)2、 CdNH-C〗-C6 烷基、（：(=0)0(：】-C6 烷基、〇C(=0)Cl _C6 烷基、 OC! -c6 烷基、sq -c6 烷基、c3 -c6 環烷基、（ch2 )m c3 _c6 環烷基、 c3-c6環烯基、（CH2)mC3-C6環烯基、c2_c6烯基、c2_c6炔基、 Αη、（CH2)mAri、苯基、吡啶基、吡咯基、（CH2)m咪唑基' (CH2)，)^畊基、呋喃基、嘧吩基、（CH2)m^唑基、（cH^m異 ^ ^ (CH2)m，t ^ . (CH2)m^ ^ ^ . (CH2)m^ ^ . (chV). 峨略基、（CH2)mP比。定基或仰‘哺$基’該環烧基與該環稀 基係視情況含有一或兩個獨立選自〇、N&s之雜原子，且 該烷基、環烷基、環烯基、烯基、炔基、 -基、異十坐基”塞唾基、異她、苯基、：：、 吡啶基或嘧啶基係視情況被一或兩個基團取代，取代基獨 立選自〇H、函素、氰基、甲基、乙基或三氟甲基，立中爪 為零、或娜和彼等所連接之環碳原子一起形成 5-或6-員稠合環，該環可為飽和、不飽和或芳族，其係視情 況含有-或兩個獨立選自〇、咖之雜原子，且其係視情 況被齒素、巧叫狀基取代；r^h、_素㈣㈣ 烧基^與〜係獨立為H、CN、*素、cF3、〇CF3、OCl_C3 132252 200914452 烷基或q -Q烷基，所有該q -C3烷基與該Ci _C6烷基視情況 被一或兩個基團取代，取代基獨立選自OH、鹵素、q 烷基、oq-q烷基或三氟甲基；χ = 〇或s; γ為〇或8; 或〇;化為匸丨-心烷基、（CHR^wC^-Q環烷基、（CHR6)WCH2C3-C6 % 烷基、CH2(CHR6)WC3-Cy^烷基、Cr6=ch_C3_C6環烷基、 ch=cr6 -c3 -c6 環烷基、(CHr6 )w C5 夂環烯基、Ch2 (CHR丄% % 烯基、C2-C6 烯基、c2-C6 炔基、Ari、（CHR6)wAr】、 CH2 (CHR6 )w Αη 或（CHR6 )w CH2 Ari，其中 w = 〇 3，Ari 為 5_ 至 i〇_ 員單或雙環狀芳族基團，視情況含有i _ 4個獨立選自N、〇 及s之％雜原子，為氫或Ci &烷基；其中全部環烷基與 %烯基係視情況含有一或兩個獨立選自N、〇及s之環雜原 子八中在Rl，R2，R3，汉4，R5，R_6或Ari中之全部烷基、環烷 基、稀基、環烯基、雜環烧基、雜環稀基、块基、芳基及 雜芳基係視情況被—或兩個取代基取代，取代基獨立選自Wherein Ar is a 1,2-fused six-membered ring aromatic group having a substituent core as defined below and 112, and containing zero or one ring nitrogen atom; wherein R) and R2 are independently Η, CN , halogen, CH2CN, OH, N02, ch2f, chf2, cf3, cf2cf3, Cl_C6 alkyl, c(=0)Ci_C6 alkyl, NH-C-C6 alkyl, NHCtCOC!-C6 alkyl, C(=〇 n(CH3)2, C(=〇)N(Et)2, CdNH-C〗-C6 alkyl, (:(=0)0(:]-C6 alkyl, 〇C(=0)Cl _C6 Alkyl, OC!-c6 alkyl, sq-c6 alkyl, c3 -c6 cycloalkyl, (ch2)m c3 _c6 cycloalkyl, c3-c6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2_c6 alkenyl, c2_c6 alkynyl, Αη, (CH2) mAri, phenyl, pyridyl, pyrrolyl, (CH2)m imidazolyl '(CH2),) cultivating, furyl, pyrenyl, (CH2) m^zolyl, (cH^miso^^(CH2)m,t ^ . (CH2)m^ ^ ^ . (CH2)m^ ^ . (chV). 峨 基, (CH2)mP ratio. Or the base of the ring and the ring-based base optionally contain one or two heteroatoms independently selected from hydrazine, N&s, and the alkyl, cycloalkyl, cycloalkenyl, alkene Base, alkynyl group, base group The base, iso-, phenyl, ::, pyridyl or pyrimidinyl is optionally substituted by one or two groups, the substituents being independently selected from 〇H, pectin, cyano, methyl, ethyl or trifluoro a methyl group, a neutral claw of zero, or a ring of carbon atoms bonded to the ring to form a 5- or 6-membered fused ring, which ring may be saturated, unsaturated or aromatic, which may optionally contain - Or two heteroatoms independently selected from the group consisting of sputum and coffee, and the system is replaced by a dentate or a crypto-like group as the case may be; r^h, _-(4) (4), and the group is independently H, CN, *, cF3, 〇CF3, OCl_C3 132252 200914452 alkyl or q-Q alkyl, all of the q-C3 alkyl and the Ci_C6 alkyl are optionally substituted by one or two groups, the substituents being independently selected from OH, halogen, q alkyl, oq-q alkyl or trifluoromethyl; χ = 〇 or s; γ is 〇 or 8; or 〇; converted to 匸丨-heart alkyl, (CHR^wC^-Q cycloalkyl, (CHR6)WCH2C3-C6 % alkyl, CH2(CHR6)WC3-Cy^alkyl, Cr6=ch_C3_C6 cycloalkyl, ch=cr6-c3-c6 cycloalkyl, (CHr6)w C5 anthracenyl, Ch2 (CHR丄% % alkenyl, C2-C6 alkenyl, c2-C6 alkynyl, Ari, (CHR6) wAr), CH2 (CHR6 )w Αη or (CHR6 )w CH2 Ari, where w = 〇3, Ari is a 5_ to i〇_ member or a bicyclic aromatic group, optionally containing i _ 4 independently selected from N, 〇 and s% of a hetero atom, which is hydrogen or Ci &alkyl; wherein all of the cycloalkyl and % alkenyl groups optionally contain one or two ring heteroatoms independently selected from N, hydrazine and s. , R2, R3, Han 4, R5, R_6 or Ari all alkyl, cycloalkyl, dilute, cycloalkenyl, heterocycloalkyl, heterocyclic, heterocyclic, aryl and heteroaryl Substituted by - or two substituents, the substituents are independently selected from

R2R2

I 132252 200914452 其中W與Z之至少一個為n; 其中後文以”胺環"所表示之部份基團 R,I 132252 200914452 wherein at least one of W and Z is n; wherein the group R represented by the "amine ring" is hereinafter,

為下文基團A或B之For the group A or B below

AA

，其中Ar為1，2-稠合六員環芳族基團，帶有 如下文定義之取代基心與^’且含有零、—或兩個環 子； μWherein Ar is a 1,2-fused six-membered ring aromatic group having a substituent core as defined below and containing zero, or two rings;

\ ，其中Ar為丨，2_稍合六員環芳族基團，帶有如下 文定義之取代基心與尺2，且含有零、一或兩個環氮原子； 其中心與心係獨立為H、CN、_素、ch2CN、OH、n〇2、 CH2F、chf2、CF3、CF2CF3、Ci_c6烧基、CK))Ci Cw基2、 NH-Cl -C6 烧基、NHC(=0)Cl -c6 烧基、C(=0)N(CH3 )2、c(,N(Et)2、 CK^NH-CrCe 烷基、（：(=0)0(：〗-C6 烷基、〇c(=〇)c丨-c6 烷基、 OC] -c6 烷基、sc! -c6 烷基、c3 -c6 環烷基、（Ch2 )m c3 _c6 環烷基' C3-C^烯基、（CH2)mC3-C6環烯基、c2-C6烯基、c2-c6炔基、 、（CH2)mAri、苯基、吡啶基、吡咯基、（CH2)m味唑基、 (⑶丄吡畊基、呋喃基、嘧吩基、（CH2)m噚唑基、（CH2)n^ Π2252 -11 - 200914452 咩唑基、（CH2)m4唑基、（CH2)m異噻唑基、（CH2)m苯基、（CH2k 吡咯基、（CH2)„^t啶基或（CH2)m嘧啶基，該環烷基與該環稀 基係視情況含有一或兩個獨立選自〇、N及s之雜原子，且 該烧基、環烧基、環烯基、稀基、炔基、咪嗤基、峨畊基、 呤唑基、異噚唑基、噻唑基、異嘧唑基、苯基、吡咯基、 峨α定基或13密σ定基係視情況被一或兩個基團取代，取代基獨 立選自ΟΗ、鹵素 '氰基、曱基、乙基或三氟甲基，其中爪 為零、1或2 ;或心與&和彼等所連接之環碳原子一起形成 5-或6-員稠合環，該環可為飽和、不飽和或芳族，其係視情 況含有一或兩個獨立選自〇、N及S之雜原子，且其係視情 況被鹵素、cf34Ci-c3烷基取代；r，為H、鹵素、CF34Ci_C3 烧基’ R3與r4係獨立為Η、CN、鹵素、CF3、OCF3、〇(：丨_c3 烧基或Cl — C6烧基，所有該C1-C3烷基與該C丨_c6烷基視情況 被一或兩個基團取代，取代基獨立選自OH、鹵素、Ci _c3 烧基、〇Cl_C3烷基或三氟甲基；x = 〇或S; Y為Ο或s; q=i 或 〇 ’ R5 為 -c6 烷基、（chr6 )w c3-c6 環烷基、（CHr6 )w Ch2 C3 七6 環烷基、CHdCHR^CVC^烷基、CR6=CH_C3_Cyf 烷基、 CH—CR6 _C3 _C6 環烷基、（CHR6 )w Q _C6 環烯基、CH2 (CHR6 )w q % % 烯基、C2-C6 烯基、C2-C6 炔基、Ari、（CHR6)wAri、 CH2(CHR6)wAri 或（chr6)wCH2 Αη ’其中 w = 〇 _ 3，Ar,為 5-至 i〇_ 員單或雙環狀芳族基團，視情況含有1 - 4個獨立選自N、〇 及S之％雜原子；心為氫或Ci a烷基；其中全部環烷基與 環烯基係視情況含有一或兩個獨立選自N、0及S之環雜原 子v、中在Ri，Κ·2，尺3，^，&，心或Ari中之全部烧基、環燒 132252 -12· 200914452 基1基、環婦基、雜環烧基、雜環缔基、快基、芳基及 雜方基係視情況被-或兩個取代基取代，取代基獨立選自 c】-c3 烧基、齒素、0H、0Me、SMe、CN、cH2Mzwf 其中全部環院基與雜環院基係另外視情況被無論是環外碳 -碳雙鍵錢基取代；且其中浠基與炔基亦另外視情況被苯 基或C3-C6環烧基取代，及所有其藥學上可接受之鹽。此種 化合物為鉀通道調節劑。 於另—項具體實施例中，本發明係提供—種組合物，其 包含藥學上彳接受之載劑及下列之至少一 # : i)藥學上有 效置之式I化合物，與ii)其藥學上可接受之鹽、醋或前體藥 物。 於又另一項具體實施例中，本發明係提供一種預防或治 療受鉀通道調節所影響之疾病或病症之方法，其包括對有 而要之病患投予治療上有效量之式〗化合物或其鹽、酯或前 體藥物。 ^ 本發明係包括本發明化合物之所有互變異構物與鹽，以 及所有立體異構形式。本發明亦包括其中一或多個原子係 被其放射性同位素置換之所有本發明化合物。 本發明係提供或意欲涵蓋上文式I化合物，其中 ⑺q-R5 為各下列者：nhc(=o)r5、nhc(=o)or5、nhc(=s)r5、 NHC(=S)SR5、NHC〇=S)OR5 及 nhc(=o)sr5。 因此’於一項具體實施例中，本發明係提供式I化合物， 其中 NH-C(=X)-(Y)q_R5 為 NHC(=〇)R5。 於另一項具體實施例中，本發明係提供式I化合物，其中 132252 200914452 NH-C(=X)-(Y)q-R5 為 NHC(=S)R5 〇 於另一項具體實施例中，本發明係提供式I化合物，其中 NH-C(=X)-(Y)q-R5 為 NHC(=S)SR5。 於另一項具體實施例中，本發明係提供式I化合物，其中 NH-C(=X)-(Y)q-R5 各為 NHC(=0)〇R5。 於另一項具體實施例中，本發明係提供式I化合物，其中 NH-C(=X)-(Y)q-R5為NHC(=S)OR5。 於另一項具體實施例中，本發明係提供式I化合物，其中 NH-C(=XHY)q-R5 為 NHC(=0)SR5。 於一項亞屬具體實施例中’本發明係提供式I化合物，其 中胺環為基團A ，且NH-C(=X)-(Y)q-R5為NHC(=0)R5或 NHC(=S)R5。 於另一項亞屬具體實施例中’本發明係提供式I化合物， 其中胺環為基團A，且NH-C(=XHY)q-R5為NHC(=0)SR5或 NHC(=S)OR5 〇 於另一項亞屬具體實施例中’本發明係提供式〗化合物， 其中胺環為基團A，且NH-C(=X)-(Y)q-R5為NHC(=0)0R5或 NHC(=S)SR5。 於另一項亞屬具體實施例中’本發明係提供式I化合物， 其中胺環為基團B，且丽_C(=X)_⑺q_R5為NHC(=〇)R5或 NHC(=S)R5。 於另一項亞屬具體實施例中，本發明係提供式I化合物， 其中胺環為基團B，且NH-C(=XHY)q _R5為NHC(=0)SR5或 NHC(=S)OR5 ο 132252 • 14- 200914452 於另一項亞屬具體實施例中，本發明係提供式i化合物， 其中胺環為基團B，且NH-C(=X)-(Y)q-R5為NHC(=0)0R5或 NHC(=S)SR5。 於另一項亞屬具體實施例中，本發明係提供下文式IA1 化合物。\ , wherein Ar is 丨, 2_ is a six-membered ring aromatic group, has a substituent core as defined below and a ruler 2, and contains zero, one or two ring nitrogen atoms; its center is independent of the heart H, CN, _, ch2CN, OH, n〇2, CH2F, chf2, CF3, CF2CF3, Ci_c6 alkyl, CK)) Ci Cw base 2, NH-Cl-C6 alkyl, NHC (=0) Cl -c6 alkyl, C(=0)N(CH3)2, c(,N(Et)2, CK^NH-CrCe alkyl, (:(=0)0(:〗-C6 alkyl, 〇c (=〇)c丨-c6 alkyl, OC]-c6 alkyl, sc!-c6 alkyl, c3 -c6 cycloalkyl, (Ch2)m c3 _c6 cycloalkyl 'C3-C^ alkenyl, ( CH2) mC3-C6 cycloalkenyl, c2-C6 alkenyl, c2-c6 alkynyl, (CH2) mAri, phenyl, pyridyl, pyrrolyl, (CH2)m-azozolyl, ((3) pyridinium ,furanyl,pyrimenyl,(CH2)moxazolyl,(CH2)n^ Π2252 -11 - 200914452 oxazolyl, (CH2)m4azolyl, (CH2)misothiazolyl, (CH2)m benzene a group, a (CH2k pyrrolyl group, a (CH2) oxazide group or a (CH2)m pyrimidinyl group, the cycloalkyl group and the ring-dense group optionally containing one or two independently selected from the group consisting of ruthenium, N and s Atom, and the alkyl group, cycloalkyl group, cycloalkenyl group Dilute, alkynyl, imipenyl, hydrazine, carbazolyl, isoxazolyl, thiazolyl, isopyrazolyl, phenyl, pyrrolyl, 峨α-decyl or 13-denier-based group Or two groups substituted, the substituents being independently selected from the group consisting of hydrazine, halogen 'cyano, decyl, ethyl or trifluoromethyl, wherein the paw is zero, 1 or 2; or the heart is attached to & The ring carbon atoms together form a 5- or 6-membered fused ring which may be saturated, unsaturated or aromatic, optionally containing one or two heteroatoms independently selected from the group consisting of ruthenium, N and S, and Substituted by halogen, cf34Ci-c3 alkyl; r, H, halogen, CF34Ci_C3 alkyl 'R3 and r4 are independently Η, CN, halogen, CF3, OCF3, 〇 (: 丨_c3 alkyl or Cl — C6 alkyl, all of the C1-C3 alkyl and the C丨_c6 alkyl are optionally substituted by one or two groups, the substituents being independently selected from OH, halogen, Ci_c3 alkyl, 〇Cl_C3 alkyl or Trifluoromethyl; x = 〇 or S; Y is Ο or s; q=i or 〇' R5 is -c6 alkyl, (chr6)w c3-c6 cycloalkyl, (CHr6)w Ch2 C3 VII 6 ring Alkyl, CHdCHR^CVC^alkyl, CR6=CH_C3_Cyf Base, CH-CR6 _C3 _C6 cycloalkyl, (CHR6)w Q _C6 cycloalkenyl, CH2 (CHR6) wq % % alkenyl, C2-C6 alkenyl, C2-C6 alkynyl, Ari, (CHR6) wAri, CH2(CHR6)wAri or (chr6)wCH2 Αη 'where w = 〇_ 3, Ar, is a 5- to i〇_ member mono- or bicyclic aromatic group, optionally containing 1 - 4 independently selected from N , 〇 and S% heteroatoms; the heart is hydrogen or Ci a alkyl; wherein all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms independently selected from N, 0 and S, All of the bases in Ri, Κ·2, 尺3, ^, &, heart or Ari, cyclization 132252 -12· 200914452 yl 1 base, cyclyl, heterocycloalkyl, heterocyclic phenyl, fast The aryl group, the aryl group and the heterocyclic group are optionally substituted by - or two substituents, and the substituents are independently selected from the group consisting of c]-c3 alkyl, dentate, 0H, 0Me, SMe, CN, cH2Mzwf, all of which are The heterocyclic compound system is additionally substituted by an exocyclic carbon-carbon double bond group, and wherein the thiol and alkynyl groups are additionally substituted by a phenyl or C3-C6 cycloalkyl group, and all of them are pharmaceutically Acceptable salt. Such compounds are potassium channel modulators. In another embodiment, the invention provides a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective compound of formula I, and ii) a pharmaceutical thereof An acceptable salt, vinegar or prodrug. In yet another embodiment, the invention provides a method of preventing or treating a disease or condition affected by modulation of a potassium channel, comprising administering to a patient in need thereof a therapeutically effective amount of a compound Or a salt, ester or prodrug thereof. ^ The invention includes all tautomers and salts of the compounds of the invention, as well as all stereoisomeric forms. The invention also includes all compounds of the invention in which one or more atomic systems are replaced by their radioisotopes. The present invention provides or intends to encompass a compound of formula I above, wherein (7) q-R5 are each of the following: nhc(=o)r5, nhc(=o)or5, nhc(=s)r5, NHC(=S)SR5, NHC〇=S)OR5 and nhc(=o)sr5. Thus, in one embodiment, the invention provides a compound of formula I, wherein NH-C(=X)-(Y)q_R5 is NHC(=〇)R5. In another embodiment, the invention provides a compound of formula I, wherein 132252 200914452 NH-C(=X)-(Y)q-R5 is NHC(=S)R5 in another embodiment The present invention provides a compound of formula I wherein NH-C(=X)-(Y)q-R5 is NHC(=S)SR5. In another specific embodiment, the invention provides a compound of formula I, wherein each of NH-C(=X)-(Y)q-R5 is NHC(=0)〇R5. In another embodiment, the invention provides a compound of formula I, wherein NH-C(=X)-(Y)q-R5 is NHC(=S)OR5. In another embodiment, the invention provides a compound of formula I, wherein NH-C(=XHY)q-R5 is NHC(=0)SR5. In a sub-specific example, the invention provides a compound of formula I wherein the amine ring is a group A and NH-C(=X)-(Y)q-R5 is NHC(=0)R5 or NHC (=S) R5. In another sub-specific embodiment, the invention provides a compound of formula I wherein the amine ring is group A and NH-C(=XHY)q-R5 is NHC(=0)SR5 or NHC (=S ORR 〇 In another sub-specific embodiment, the invention provides a compound wherein the amine ring is a group A and NH-C(=X)-(Y)q-R5 is NHC (=0) ) 0R5 or NHC (=S) SR5. In another sub-specific embodiment, 'the invention provides a compound of formula I, wherein the amine ring is group B, and 丽_C(=X)_(7)q_R5 is NHC(=〇)R5 or NHC(=S)R5 . In another sub-specific embodiment, the invention provides a compound of formula I wherein the amine ring is group B and NH-C(=XHY)q_R5 is NHC(=0)SR5 or NHC(=S) OR5 ο 132252 • 14- 200914452 In another sub-specific embodiment, the invention provides a compound of formula i wherein the amine ring is group B and NH-C(=X)-(Y)q-R5 is NHC (=0) 0R5 or NHC (= S) SR5. In another sub-specific embodiment, the invention provides a compound of formula IA1 below.

IA1 於另一項亞屬具體實施例中，本發明係提供下文式IA2 化合物。IA1 In another sub-specific embodiment, the invention provides a compound of formula IA2 below.

於另一項亞屬具體實施例中，本發明係提供下文式IA3 化合物。In another sub-specific embodiment, the invention provides a compound of formula IA3 below.

IA3 於另一項亞屬具體實施例中，本發明係提供下文式IA4 化合物。 132252 -15 - 200914452IA3 In another sub-specific embodiment, the invention provides a compound of formula IA4 below. 132252 -15 - 200914452

於另一項亞屬具體實施例中，本發明係提供下文式IA5 化合物。In another sub-specific embodiment, the invention provides a compound of formula IA5 below.

於另一項亞屬具體實施例中，本發明係提供下文式IB1 化合物。In another sub-specific embodiment, the invention provides a compound of formula IB1 below.

IB1 於另一項亞屬具體實施例中，本發明係提供下文式IB2 化合物。IB1 In another sub-specific embodiment, the invention provides a compound of formula IB2 below.

IB2 於另一項亞屬具體實施例中，本發明係提供下文式IB3 化合物。 132252 -16- 200914452IB2 In another sub-specific embodiment, the invention provides a compound of formula IB3 below. 132252 -16- 200914452

ΙΒ3 本發明係提供下文式ΙΒ4 於另一項亞屬具體實施例中 化合物。ΙΒ3 The present invention provides a compound of the following formula ΙΒ4 in another sub-specific embodiment.

ΙΒ4 本發明係提供下文式ΙΒ5 於另一項亞屬具體實施例中 化合物。ΙΒ 4 The present invention provides a compound of the following formula ΙΒ5 in another sub-specific embodiment.

R5R5

IB5IB5

於-項更特殊亞屬具體實施例中，本發明係提供任何式 ΙΑ1-ίΑ5化合物，其中W與Z均為N。 於另一項更特殊亞屬具體實 式IA1-IA5化合物，其中WgN 於另一項更特殊亞屬具體實 式IA1-IA5化合物，其中…為匸 於另一項更特殊亞屬具體實 式ΙΑΛ-ΙΑ5化合物，其中R，為只 施例中，本發明係提供任何 ，且Z為C。 施例中，本發明係提供任何 ，且Z為N。 施例中，本發明係提供任何 、鹵素、CT3或曱基。 132252 -17· 200914452 式麗A5化合物=具體實施例中，本發明係提供任何 於另-項更接均❹，且R，為H、F或曱基。 式刪B5化合體實施例中’本發明係提供任何 物，其中|與2均為N。 二特殊亞屬具體實施例中，本發明係提供任何 5物，其中，且。 於另一項更特殊亞屬具體實施财，本發明In a more specific sub-specific embodiment of the invention, the invention provides any compound of the formula ΙΑ1-ίΑ5 wherein both W and Z are N. In another more specific subgenus, a specific compound of the formula IA1-IA5, wherein WgN is in another more specific subgenus specific compound IA1-IA5, wherein ... is a specific subgenus specific ΙΑΛ - ΙΑ5 compound, wherein R, in the case of only the examples, the invention provides any, and Z is C. In the examples, the invention provides any, and Z is N. In the examples, the invention provides any, halogen, CT3 or sulfhydryl groups. 132252 -17· 200914452 Formula A5 Compound = In a specific embodiment, the present invention provides any further homogeneity, and R is H, F or thiol. In the embodiment of the present invention, the present invention provides any of the following, wherein | and 2 are both N. In a particular subgenus embodiment, the invention provides any of the five, wherein, and. The invention is embodied in another more specific subgenus

式则5化合物，其中W為。，且Z為N。 、於另-項更特殊亞屬具體實施例中’本發明係提供任何 式IB1-IB5化合物，其中R，為H、齒素、cf3或甲基。 ；貞更特殊亞屬具體實施例中，本發明係提供任何 式职-脱化合物，其中均為n，且r，為h、f或甲基。 於—項更特殊亞屬具體實施例中，本發明係提供或意欲 涵蓋任何式IA1_IA5化合物，其中X為〇，q叫，γ為〇二且 R5 為 Ci -c6 炫基、（CHR6 )w c3 _c6 環烧基、（CHr6 )w CH2 Q 夂環燒 基或 CHdCHR^wQ-Cy^烷基。 於又更特殊亞屬具體實施例中，本發明係提供或意欲涵 蓋任何式IA1-IA5化合物，其中X為〇; q = i; γ為〇;心為c】& 烷基、（CHR6)WC3-C6 環烷基、（CHR6)WCH2C3-C6 環烷基或 CH2(CHR6)WC3-C6 環烷基；且 R^h、CF3或鹵素。 於又更特殊亞屬具體實施例中’本發明係提供或意欲涵 蓋任何式IA1-IA5化合物，其中X為〇; q=1; γ為〇; %為被 甲氧基、甲硫基或鹵素取代之q -C6烷基；且心為η、CF3 或鹵素。 132252 -18- 200914452 於另一項亞屬具體實施例中’本發明係提供或意欲涵蓋 任何式IA1-IA5化合物，其中X為〇，q=1，γ為〇，且心為 CR6=CH-C3-C6環烷基、CHCR^-CVQ環烷基、（CHR6)WC5-C6 環烯基、ch2(chr6)wc5-c6環烯基、C2-C6烯基或c2-c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 名人’函蓋任何式IA1-IA5化合物，其中X為〇，，γ為〇， 且 R5 為 Ar!、（CHR6)wAri、CHdCHI^XvArAKHR^CI^Arj。 於另一項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋任何式IA1_IA5化合物，其中X為〇，q=l ,Υ為S， 且 R5 為 C! -C6 烷基、（CHR6 )w C3 -C6 環烷基、（CHR6 )w CH2 C3 -C6 環燒基或CH2 (chr6 )w c3 -c6環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1_IA5化合物，其中X為〇，q=l，Y為S， 且心為CR6=CH-C3-C6環烷基、CH=CR6-C3-C6環烷基、 (CHR6 )w c5 -c6 環烯基、ch2 (CHr6 )w c5 _c6 環烯基、c2 _c6 烯基或 c2 -C6炔基。 於另一項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋任何式认1-1八5化合物，其中X為0，q=i，Y為S， 且 R5 為 Ari、（CHR6)wAri、CH2(CHR6)wAr丨或（CHR6)wCH2Ari。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵盍任何式IA1_IA5化合物，其中χ為〇 , q =零且^為Formula 5 compounds wherein W is. And Z is N. In a further specific sub-specific embodiment, the invention provides any compound of the formula IB1-IB5 wherein R is H, dentate, cf3 or methyl. In a particular embodiment of the invention, the invention provides any formula-de-compound wherein all are n and r is h, f or methyl. In a more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1_IA5 wherein X is 〇, q is γ, γ is 〇 and R5 is Ci-c6 炫, (CHR6)w c3 _c6 cycloalkyl, (CHr6)w CH2 Q fluorenyl or CHdCHR^wQ-Cy^alkyl. In a more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1-IA5 wherein X is hydrazine; q = i; γ is deuterium; heart is c] & alkyl, (CHR6) WC3-C6 cycloalkyl, (CHR6)WCH2C3-C6 cycloalkyl or CH2(CHR6)WC3-C6 cycloalkyl; and R^h, CF3 or halogen. In a more specific sub-specific embodiment, 'the invention provides or intends to encompass any compound of formula IA1-IA5 wherein X is deuterium; q=1; γ is deuterium; % is methoxy, methylthio or halogen Substituted q-C6 alkyl; and the heart is η, CF3 or halogen. 132252 -18- 200914452 In another sub-specific embodiment, 'the invention provides or intends to encompass any compound of formula IA1-IA5, wherein X is 〇, q=1, γ is 〇, and the heart is CR6=CH- C3-C6 cycloalkyl, CHCR^-CVQ cycloalkyl, (CHR6)WC5-C6 cycloalkenyl, ch2(chr6)wc5-c6 cycloalkenyl, C2-C6 alkenyl or c2-c6 alkynyl. In another more specific sub-specific embodiment, the invention provides or means the name of any compound of formula IA1-IA5 wherein X is deuterium, γ is deuterium, and R5 is Ar!, (CHR6) wAri , CHdCHI^XvArAKHR^CI^Arj. In another more specific sub-specific embodiment, the invention provides or intends to encompass any compound of the formula IA1_IA5 wherein X is 〇, q=l, Υ is S, and R5 is C!-C6 alkyl, (CHR6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl or CH 2 (chr 6 ) w c 3 -c 6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or is intended to encompass any compound of formula IA1_IA5 wherein X is hydrazine, q=l, Y is S, and the core is CR6=CH-C3-C6 naphthenic And CH=CR6-C3-C6 cycloalkyl, (CHR6)w c5-c6 cycloalkenyl, ch2(CHr6)w c5-c6 cycloalkenyl, c2_c6 alkenyl or c2-C6 alkynyl. In another more specific sub-specific embodiment, 'the invention provides or intends to encompass any compound of formula 1-1,5, wherein X is 0, q=i, Y is S, and R5 is Ari, (CHR6 ) wAri, CH2(CHR6)wAr丨 or (CHR6)wCH2Ari. In another more specific sub-specific embodiment, the invention provides or is intended to encompass any compound of formula IA1_IA5 wherein χ is 〇, q = zero and ^ is

Cl _C6 烷基、（CHR6 )w C3 -C6 環烷基、（CHR6 )w CH2 C3 -c6 環烷基或 ch2(chr6)wC3_C6環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 132252 -19- 200914452 欲涵蓋任何式IA1_IA5化合物，其中χ為〇;£}=零；R5為 烷基 ' (CHR6)wC3-C6 環烷基、（CHR6)wCH2C3_C6 環烷基或 CH2(CHR6)WC3-C6環烷基；且&為鹵素。 於另項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1-IA5化合物，其中X為〇; (1 =零；r5為 烷基' (CHR^wC^q環烷基、（CHR6)wCH2C3_C6環烷基或 C^CCHR^wC^-C6環烷基；R·為鹵素或^七烷基；且心為鹵 素。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式认1-1八5化合物，其中X為〇，q =零，且心為 CR6=CH_C3_C6環烷基、ch=civc3-c6環烷基、（CHR6)wC5_C6 矛、希基CH2 (chr6 )wC5 -C6環稀基、c2 -C6稀基或c2 -C6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1_IA5化合物，其中X為〇，（？=零，且化為Cl _C6 alkyl, (CHR6 ) w C3 - C6 cycloalkyl, (CHR6)w CH2 C3 - c6 cycloalkyl or ch2(chr6) wC3_C6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends 132252-19-200914452 to encompass any compound of formula IA1_IA5 wherein χ is 〇; £}=zero; R5 is alkyl '(CHR6)wC3 -C6 cycloalkyl, (CHR6)wCH2C3_C6 cycloalkyl or CH2(CHR6)WC3-C6 cycloalkyl; and & In a further, more specific sub-specific embodiment, the invention provides or is intended to encompass any compound of formula IA1-IA5 wherein X is hydrazine; (1 = zero; r5 is alkyl' (CHR^wC^q cycloalkyl) , (CHR6)wCH2C3_C6 cycloalkyl or C^CCHR^wC^-C6 cycloalkyl; R· is halogen or octadecyl; and the heart is halogen. In another more specific sub-specific embodiment, The invention provides or intends to encompass any compound of formula 1-1,8, wherein X is 〇, q = zero, and the core is CR6=CH_C3_C6 cycloalkyl, ch=civc3-c6 cycloalkyl, (CHR6)wC5_C6 spear, Hiki CH2 (chr6) wC5-C6 cycloaliphatic, c2-C6 dilute or c2-C6 alkynyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass any of the compounds of formula IA1_IA5, Where X is 〇, (?=zero, and turned into

Ari、（CHR^wAq、CHdCHR^Ai^CHRdwC^Ar!。 、另項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1_IA5化合物，其中χ為s,q=1，Y為〇， ^ R5 為 CrQ 烷基、（CHR6)wC3_C6 環烷基、（CHR6)wCH2C3 _C6 環燒基或CH2 (CHR6 )w C3 -C6環烷基。 ;另項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1-IA5化合物，其中χ為s，q=l Y為〇， 且 R5 為 cr6=ch-c3-c6 環烷基、ch=cr6-c3-c6 環烷基、 )w c5 _c6 環烯基、Ch2 (CHR6 )w c5 _c6 環烯基、Q q 烯基或 c2 -C6炔基。 132252 -20- 200914452 於另一項更特殊亞屬具體實施例中，本發明係提供或意 右人’函盍任何式1A1-IA5化合物，其中X為S，q = 1 , γ為〇 , 且心為 Ari、（CHR6)wAri、CH2(CHR6 )wCH2Ari。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式认1-认5化合物’其中X為S , q =零，且^為Ari, (CHR^wAq, CHdCHR^Ai^CHRdwC^Ar!., a more specific sub-general embodiment, the invention provides or intends to encompass any of the compounds of formula IA1_IA5, wherein χ is s, q=1, Y Is 〇, ^ R5 is CrQ alkyl, (CHR6) wC3_C6 cycloalkyl, (CHR6) wCH2C3 _C6 cycloalkyl or CH2 (CHR6) w C3 - C6 cycloalkyl. The present invention provides or intends to encompass any compound of the formula IA1-IA5 wherein χ is s, q=l Y is 〇, and R5 is cr6=ch-c3-c6 cycloalkyl, ch=cr6-c3-c6 cycloalkane Base, ) w c5 _c6 cycloalkenyl, Ch 2 (CHR 6 ) w c5 _c6 cycloalkenyl, Q q alkenyl or c 2 -C 6 alkynyl. 132252 -20- 200914452 In another more specific sub-specific embodiment, the invention provides or is intended to mean any compound of formula 1A1-IA5 wherein X is S, q = 1 and γ is 〇, and The heart is Ari, (CHR6) wAri, CH2(CHR6)wCH2Ari. In another more specific sub-specific embodiment, the invention provides or is intended to encompass any formula 1 - recognize 5 compound 'where X is S, q = zero, and ^ is

Cl Α 烧基、（CHR6 )W C3 A 環烷基、（CHR6 )w CH2 C3 -C6 環烷基或 eH2(c：HR6)wC3-c6環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1-IA5化合物，其中X為S , q =零，且心為 cr6=ch-c3-c6環烷基、CH=CR6_C3_C6環烷基、（CHR6)wC⑸ %烯基、ch2(chr6)wc5-c6環烯基、c2-c6烯基或c2_c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵盍任何式IA1-IA5化合物’其中X為s，q =零，且尺5為 Αη、（CHR6)wAri、CH2(CHR6)wAr^(CHR6)wCH2Ari。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IAHA5化合物，其中X為S，q=1，γ為s, 且心為^夂烷基、（CHR6)wC3_C6環烷基、（CHR6)wCH2C⑸ 環烷基或CH2 (CHR6 )w c3 -c6環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1-IA5化合物，其中X為S，q=1，Ygs， 且 R5 為 CR6=CH-C3-C6 環烷基、CH=CR6-C3-C6 環烷基、 (CHR6 )w c5 -c6 環烯基、ch2 (CHR6 )w c5 _c6 環烯基、c2 烯基或 C2 -C6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 132252 •21 · 200914452 欲涵蓋任何式IA1-IA5化合物，其中X為S，q=i，Ygs, 且 R5 為 ΑΓι ' (CHR6)wAri、cH2(CHR6)wAt^(CHR6)wCH2Ari。 於一項更特殊亞屬具體實施例中，本發明係提供或意欲 涵蓋式IA-1化合物，其中χ為〇，q = i , γ為〇，且心為& 烷基、（CHR6)wC3.C6 環烷基、（CHR6)WCH2C3_C6 環烷基或 eH2(CHR6)WC3-C6環烷基。 於又更特殊亞屬具體實施例中，本發明係提供或意欲涵 蓋任何式IA-1化合物，其中又為〇; q=1; 丫為〇;且心為被 甲氧基、甲硫基或鹵素取代之c丨_c6烧基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中X為〇, q=1，丫為〇,且心為 cr6=ch-c3-c^ 烷基、CH=CR6_C3_c^t 烷基、（CHR6)wC5 _C6 環烯基、〇12(〇1116；^(：5-(：6環烯基、c2-c6烯基或c2-c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為〇，q = J，丫為〇，且&為Cl oxime, (CHR6)W C3 A cycloalkyl, (CHR6)w CH2 C3 -C6 cycloalkyl or eH2(c:HR6)wC3-c6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1-IA5 wherein X is S, q = zero, and the core is cr6=ch-c3-c6 cycloalkyl, CH=CR6_C3_C6 cycloalkyl, (CHR6)wC(5) % alkenyl, ch2(chr6)wc5-c6 cycloalkenyl, c2-c6 alkenyl or c2_c6 alkynyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1-IA5 wherein X is s, q = zero, and rule 5 is Αη, (CHR6)wAri, CH2 ( CHR6) wAr^(CHR6)wCH2Ari. In another more specific sub-specific embodiment, the invention provides or is intended to encompass any compound of the formula IAHA5 wherein X is S, q=1, γ is s, and the heart is 夂alkyl, (CHR6)wC3_C6 Cycloalkyl, (CHR6)wCH2C(5) cycloalkyl or CH2(CHR6)w c3 -c6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1-IA5 wherein X is S, q=1, Ygs, and R5 is CR6=CH-C3-C6 naphthenic Base, CH=CR6-C3-C6 cycloalkyl, (CHR6)w c5-c6 cycloalkenyl, ch2(CHR6)w c5-c6 cycloalkenyl, c2 alkenyl or C2-C6 alkynyl. In another more specific sub-specific embodiment, the invention provides or intends 132252 • 21 · 200914452 to cover any compound of formula IA1-IA5, wherein X is S, q=i, Ygs, and R5 is ΑΓι ' ( CHR6) wAri, cH2(CHR6)wAt^(CHR6)wCH2Ari. In a more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1 wherein χ is 〇, q = i, γ is 〇, and the heart is & alkyl, (CHR6) wC3 .C6 cycloalkyl, (CHR6)WCH2C3_C6 cycloalkyl or eH2(CHR6)WC3-C6 cycloalkyl. In a more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA-1, wherein is 〇; q=1; 丫 is 〇; and the heart is methoxy, methylthio or Halogen substituted c丨_c6 alkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1 wherein X is 〇, q=1, 丫 is 〇, and the heart is cr6=ch-c3-c^ Alkyl, CH=CR6_C3_c^t alkyl, (CHR6)wC5_C6 cycloalkenyl, 〇12(〇1116;^(:5-(:6cycloalkenyl, c2-c6 alkenyl or c2-c6 alkynyl). In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1, wherein χ is 〇, q = J, 丫 is 〇, and &

Ar!、（CHR6)wAri、CHdCHRdwArACCHRdwCf^Ari。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式iA-i化合物，其中χ為0，q=1，Y&s,aR5*Ar!, (CHR6) wAri, CHdCHRdwArACCHRdwCf^Ari. In another more specific sub-specific embodiment, the invention provides or is intended to encompass a compound of formula iA-i wherein χ is 0, q = 1, Y & s, aR5*

Cl -C6 院基、（chr6 )w c3 -c6 環烷基、（CHR6 )w CH2 C3 -C6 環烷基或 ch2 (chr6 )w C3 -C6 環烧基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為〇，q = i , γ為s ,且尺5為 CR6=CH-C3-C6環烷基 ' CH=CR6_C3_C6環烷基、（CHR6)wC5_c6 壞歸基、CHJCHRdwCVCV^烯基、c2-c6烯基或c2-c6炔基。 132252 -22- 200914452 另工頁爭 .. 、 、尺特殊亞屬具體實施例中，本發明係提供或意 奴叫二式IA_1化合物’其中X為〇，q = 1，Y為S，且115為 Αη、、CH2(CHR6)為或 。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 "㈡i式1a 1化合物，其中X為〇，q =零，且r5為c! -c6烷 基、（CHR6)wC3<：6環烷基、（CHRWrQ環烷基或 €H2((：HR6)wC3-C6環烷基。Cl -C6, (chr6)w c3 -c6 cycloalkyl, (CHR6)w CH2 C3 -C6 cycloalkyl or ch2(chr6)w C3 -C6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1 wherein χ is 〇, q = i , γ is s, and rule 5 is CR6=CH-C3-C6 Cycloalkyl 'CH=CR6_C3_C6 cycloalkyl, (CHR6)wC5_c6 badly cyclized, CHJCHRdwCVCV^alkenyl, c2-c6 alkenyl or c2-c6 alkynyl. 132252 -22- 200914452 Another sub-specific embodiment of the invention, the invention provides or intends to call the compound of the formula IA_1 where X is 〇, q = 1, Y is S, and 115 For Αη, CH2(CHR6) is or. In another more specific sub-specific embodiment, the invention provides or is intended to mean a compound of formula 1a, wherein X is deuterium, q = zero, and r5 is c! -c6 alkyl, (CHR6)wC3<lt;;: 6 cycloalkyl, (CHRWrQ cycloalkyl or €H2 ((: HR6) wC3-C6 cycloalkyl.

於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式1A_1化合物，其中X為〇，q =零，且心為 CR6=CH_C3_C6環烷基、CH=CR6-C3-C6環烧基、（Chr6)wc5_C6 裒稀基CH2(CHR6)WC5-C6環烯基、C2-C6烯基或（]2-(：6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為〇 , q =零，且r5為、 (CHR6)wAr! ^ C^CCH^^Ar^iCHRe^C^Arj 〇 於另項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為s，q = i，丫為〇，且心為 ci -c6 烷基、（CHR6 )wC3 環烷基、（CHR6 )wCH2 q _C6 環烷基或 CH2(CHR6)WC3-C6環烷基。 於另一項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式IA-1化合物，其中X為s，q = 1，γ為〇，且心為 CR6=CH-C3-C6 環烷基、ch=cr6-c3-c6 環烷基、（CHR6XvC5_c6 環稀基、ch2(chr6)wc5-c6環烯基、c2-c6烯基或c2_c6炔基。 於另一項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式IA-1化合物’其中X為S，q = 1，Y為〇，且心為 132252 -23- 200914452 ΑΓΐ、（CHR6)wAri、CH2(CHR6)wAi^(CHR6)wCH2Ari。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵盍式IA-1化合物，其中χ為s，q =零，且&為& &烷 基、（CHR6)wC3'C6 環烷基、（CHIMwCHA-C6 環烷基或 • CH2(CHR6)WC3-C^f烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為s，q =零，且心為cr6=chC3_C6 ( 環烷基、ch=cr6-C3-c6 環烷基、（CHR6)wC5_C6 環烯基、 CH2(CHR6)WC5-C6環烯基、c2_c6烯基或 c2_c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為s ’ q =零，且R5為、 (CHR6)wAri、CHdCHRdwAi^eHDwCt^Aq。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為s，q =丨，γ為s，且^為q 烷基、（CHR6)wC3-c6 環烷基、（chr6)wch2c3-c6 環烷基或 {j CH2(CHR6)wC3-C^ 烷基。 於另員更特殊亞屬具體貫施例中，本發明係提供或意 欲涵蓋式IA-1化合物，其中χ為s，q = i，Y*s，且心為 。 CR6 =ch-c3 -c6 環烷基、CH=CR6 _c3 _c6 環烷基、（CHR6 k Q % .環烯基、CH2(CHR6)WC5-C6環烯基、C2_Q烯基或c2_c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式IA1_IA5化合物，其中X為S，q=i，Y為s， 且 R#Ari、（CHR6)wAr丨、CH2(CHR6)wAi^(CHR6)wCH2Ari。 於另一項更特殊亞屬具體實施例中，本發明係提供或奄 132252 •24- 200914452 欲涵蓋式ffi化合物，其中x為〇，q = J，γ為〇，且R5為Cl <6 烷基、（CHR6)wC3-C6 環烷基、（CHR6)WCH2C3-C6 環烷基或 CH2(CHR6)WC3-C6環烷基。 於另一項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式IB化合物，其中χ為〇，q = !，γ為〇，且心為 CR6=CH_C3-C6環烷基、CH=CR6-C3-C6環烷基、（chr6)wc5-c6 環烯基、ch2(chr6)wc5-c6環烯基、c2-c6烯基或c2-c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IB化合物，其中χ為〇，q = i，γ為〇，且r5為Ari、 (CHR6)wAri、CH2(CHR6)wAri 或(CHR6)wCH2Ar丨。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式ro化合物，其中X為0 , q=1，丫為8，且化為^乂 烧基、（CHR6)wc3-c6 環烷基、（chr6)wch2c3-c6 環烷基或 CH2(CHR6)WC3-C4烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IB化合物，其中X為〇，q = i , γ為s，且為 cr6=ch-c3-c6環烷基、CH=CR6_C3_C6環烷基、（CHR6)WC5_C6 環烯基、ch2(chr6)wc5-c6環烯基、c2-c6烯基或c2_c6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式ffi化合物，其中X為0，q = 1，γ為S，且r5為ΑΓι、 (CHR6 )w Ar!、CH2 (CHR6 )w ΑΓι 或（CHR6 )w CH2 Αη。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式ffi化合物’其中X為〇，q =零，且r5為Cl _c6烷基、 (CHR6 )w c3 -c6 環烷基、（CHr6 )w Ch2 C3 _c6 環烷基或 Ch2 (CHR6 )w 132252 -25- 200914452 C3-C6環烷基。 於另帛更特殊亞屬具體實施例中，本發明係提供或意 :涵蓋式IB化合物’其中x為〇，q =零，且r5為Cr6=CH-C3-c6 衣燒基CH—CR6-C3-C6環燒基、（CHR6)wC5 _C6環稀基、 ch2(Chr6)wC5_c6環稀基、C2_C6烯基或C2_C6炔基。 於另項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IB化合物，其中χ為〇，q =零，且〜為私、 Χν Αη、CH2 (CHR6 )w Ar!或（CHR6 )w Ch2 ΑΓι。 於另帛更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式m化合物，其中XW，q=卜丫為〇，且〜為以 烷基、（chr^-q環院基、（CHR6)wCH2C3_c6環烧基或 CH2(CHR6)WC3-C6環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋_化合物，其中Xy，q叫，丫為〇，且仏為 CR6=CH-C3-C6m^& , CH=CR,-C3-C6it^^ , (CHR6)WC5-C6 壞歸基、Ch2(CHr6)wC5_C6環稀基、w烯基或块基。 於另-項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IB化合物，其中X為S，q=1，Y^qR5^、 (CHR6)wAri、CH^CHR^wAi^CCHR^o^Ar】。 於另-項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式迅化合物’其中X^，q =零，且R^Ci舰、In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula 1A_1 wherein X is oxime, q = zero, and the core is CR6=CH_C3_C6 cycloalkyl, CH=CR6-C3-C6 Cycloalkyl, (Chr6) wc5_C6 oxime CH2(CHR6) WC5-C6 cycloalkenyl, C2-C6 alkenyl or (]2-(:6 alkynyl). In another more specific sub-specific embodiment The present invention provides or intends to encompass a compound of formula IA-1 wherein χ is 〇, q = zero, and r5 is, (CHR6)wAr! ^ C^CCH^^Ar^iCHRe^C^Arj 另In a particular sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1 wherein χ is s, q = i, 丫 is 〇, and the heart is ci-c6 alkyl, (CHR6) wC3 cycloalkyl , (CHR6)wCH2 q _C6 cycloalkyl or CH2(CHR6)WC3-C6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1, wherein X s, q = 1, γ is 〇, and the heart is CR6=CH-C3-C6 cycloalkyl, ch=cr6-c3-c6 cycloalkyl, (CHR6XvC5_c6 cycloaliphatic, ch2(chr6)wc5-c6 ring Alkenyl, c2-c6 alkenyl or c2_c6 alkynyl. In the present invention, the invention provides or intends to encompass a compound of formula IA-1 wherein X is S, q = 1, Y is 〇, and the heart is 132252 -23- 200914452 ΑΓΐ, (CHR6) wAri, CH2 (CHR6) wAi^(CHR6)wCH2Ari. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1, wherein χ is s, q = zero, and & is && Alkyl, (CHR6)wC3'C6 cycloalkyl, (CHIMwCHA-C6 cycloalkyl or • CH2(CHR6)WC3-C^f alkyl. In another more specific sub-specific embodiment, the invention Provided or intended to encompass a compound of formula IA-1 wherein χ is s, q = zero, and the core is cr6=chC3_C6 (cycloalkyl, ch=cr6-C3-c6 cycloalkyl, (CHR6) wC5_C6 cycloalkenyl, CH2(CHR6)WC5-C6 cycloalkenyl, c2_c6 alkenyl or c2_c6 alkynyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1 wherein χ is s ' q = zero, and R5 is (CHR6)wAri, CHdCHRdwAi^eHDwCt^Aq. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA-1, wherein χ is s, q =丨γ is s, and q ^ is alkyl, (CHR6) wC3-c6 cycloalkyl, (chr6) wch2c3-c6 cycloalkyl or {j CH2 (CHR6) wC3-C ^ alkyl. In a particular embodiment of a more specific subgenus, the invention provides or is intended to encompass a compound of formula IA-1 wherein χ is s, q = i, Y*s, and the heart is . CR6 =ch-c3 -c6 cycloalkyl, CH=CR6 _c3 _c6 cycloalkyl, (CHR6 k Q % .cycloalkenyl, CH2(CHR6)WC5-C6 cycloalkenyl, C2_Q alkenyl or c2_c6 alkynyl. In a more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1_IA5 wherein X is S, q=i, Y is s, and R#Ari, (CHR6)wAr丨, CH2 ( CHR6)wAi^(CHR6)wCH2Ari. In another more specific sub-specific embodiment, the invention provides or 奄132252 •24- 200914452 to cover a compound of the formula f, wherein x is 〇, q = J, γ is 〇, and R5 is Cl <6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)WCH2C3-C6 cycloalkyl or CH2(CHR6)WC3-C6 cycloalkyl. In another more special sub In a specific embodiment, the invention provides or intends to encompass a compound of formula IB, wherein χ is 〇, q = !, γ is 〇, and the heart is CR6=CH_C3-C6 cycloalkyl, CH=CR6-C3-C6 ring Alkyl, (chr6)wc5-c6 cycloalkenyl, ch2(chr6)wc5-c6 cycloalkenyl, c2-c6 alkenyl or c2-c6 alkynyl. In another more specific sub-specific embodiment, The invention provides or intends to encompass a compound of formula IB, wherein χ is 〇, q = i, γ is 〇, and r5 is Ari, (CHR6) wAri, CH2(CHR6)wAri or (CHR6)wCH2Ar丨. In another more specific sub-specific embodiment, the invention provides or intends to encompass the formula ro a compound wherein X is 0, q=1, 丫 is 8, and is converted to a mercapto group, (CHR6)wc3-c6 cycloalkyl, (chr6)wch2c3-c6 cycloalkyl or CH2(CHR6)WC3-C4 In another specific embodiment of the subgenus, the invention provides or intends to encompass a compound of formula IB wherein X is deuterium, q = i, γ is s, and is a cr6=ch-c3-c6 ring Alkyl, CH=CR6_C3_C6 cycloalkyl, (CHR6)WC5_C6 cycloalkenyl, ch2(chr6)wc5-c6 cycloalkenyl, c2-c6 alkenyl or c2_c6 alkynyl. Another more specific sub-specific embodiment The present invention provides or intends to encompass a compound of the formula ffi wherein X is 0, q = 1, γ is S, and r5 is ΑΓι, (CHR6)w Ar!, CH2 (CHR6)w ΑΓι or (CHR6)w CH2 In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of the formula ffi wherein X is 〇, q = zero, and r5 is Cl _c6 alkyl, (CHR6 ) w c3 -c6 Cycloalkyl, (CHr6)w Ch2 C3 _c6 naphthenic Base or Ch2 (CHR6)w 132252 -25- 200914452 C3-C6 cycloalkyl. In a further particular sub-specific embodiment, the invention provides or is intended to encompass a compound of formula IB wherein x is deuterium, q = zero, and r5 is Cr6=CH-C3-c6 alkylene CH-CR6- C3-C6 cycloalkyl, (CHR6) wC5_C6 cycloaliphatic, ch2(Chr6)wC5_c6 cycloaliphatic, C2_C6 alkenyl or C2_C6 alkynyl. In a further, more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IB wherein χ is 〇, q = zero, and 〜 is private, Χν Αη, CH2(CHR6)w Ar! or (CHR6 )w Ch2 ΑΓι. In a particular embodiment of the invention, the invention provides or intends to encompass a compound of formula m wherein XW, q = dip is 〇, and 〜 is alkyl, (chr^-q ring, ( CHR6) wCH2C3_c6 cycloalkyl or CH2(CHR6)WC3-C6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound wherein Xy, q is called 丫And 仏 is CR6=CH-C3-C6m^&, CH=CR, -C3-C6it^^, (CHR6)WC5-C6 badly homing, Ch2(CHr6)wC5_C6 ring-dilute, w-alkenyl or block In a further specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IB, wherein X is S, q = 1, Y^qR5^, (CHR6) wAri, CH^CHR^wAi ^CCHR^o^Ar. In the other-specific sub-specific embodiments, 'the invention provides or intends to cover a compound of the formula' wherein X^, q = zero, and R^Ci ship,

(CHR6)WC3-C6環燒基、（CHR6)wCH2C3_C6環烧基或CH2(哪6)w C3 _C6環烧基。 W 於另-項更特殊亞屬具體實施例中，本發明係提供或意 132252 -26· 200914452 欲涵蓋式IB化合物，其中乂為8，9 =零，且R5&CR6=CHC3_C6 環燒基、ch=cr6-c3-c6環烷基、（chr6)wc5_c6環烯基、 CH2(CHR6)WC5-C6環烯基、c2_c6烯基或 C2_C6炔基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IB化合物，其中χ為s，q =零，且r5為Ar_i ' (CHReXvAr!、CHdCHRdwAi^CCHR^Ct^Ari。(CHR6) WC3-C6 cycloalkyl, (CHR6) wCH2C3_C6 cycloalkyl or CH2 (next 6) w C3 _C6 cycloalkyl. In a further specific sub-specific embodiment of the invention, the invention provides or intends to cover a compound of formula IB, wherein 乂 is 8,9 = zero, and R5&CR6=CHC3_C6 cycloalkyl, Ch=cr6-c3-c6 cycloalkyl, (chr6)wc5_c6 cycloalkenyl, CH2(CHR6)WC5-C6 cycloalkenyl, c2_c6 alkenyl or C2_C6 alkynyl. In another more specific sub-specific embodiment, the invention provides or is intended to encompass a compound of formula IB wherein χ is s, q = zero, and r5 is Ar_i ' (CHReXvAr!, CHdCHRdwAi^CCHR^Ct^Ari.

於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式ffi化合物，其中X為S，q=1，¥為8，且心為^夂 烷基、（CHR6)WC3-C6 環烷基、（CHR6)WCH2C3-C6 環烷基或 CH2 (CHR6 )w C3 -c6 環烧基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IB化合物，其中χ為s，q = i ’ γ為s，且^為 cr6=ch-c3-c6 環烷基、ch=cr6-c3-c^ 烷基、（CHR6)wC5_C6 環晞基、ch2(chr6)wc5_C6環稀基、C2_C6烯基或c2_c6块基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 右人涵蓋式IB化合物，其中χ為s，q = i，γ為s，且心為An、 (CHR6)wAri、CH2(CHR6)wAri 或(CHR6)wCH2Ari。 π乃一孭更特殊 欲涵蓋式 ΙΑ1、ΙΑ2、ΙΑ3、ΙΑ4 或1Β5化合物，其中X為0，q 基或（CHR6)WC3-C6環烷基。 IA5、IB1、ffi2、IB3、IB41，Y為ο，且I為c丨-C6烷 於另一項更特殊亞屬具體實施例中，本發明係提供或意 右人涵盍式 IA1、IA2、IA3、IA4、IA5、lm、lm、如、iB4 或ΪΒ5化合物，其中x為s,a=i ,γ或Q p D 〇 八甲入马s，q l，y為s，且r5aCi_C6烷基 132252 -27- 200914452 或（CHR6)WCVC6環烷基。 二1更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式IA1 ' ΤΛ 、1Α3、ΙΑ4、ΙΑ5、ΙΒ1、ΙΒ2、ΙΒ3、ΙΒ4 或IB5化合物，复中 上 “甲入為8,9=:1，¥為0，且115為（：1-(：6烷基 或（CHR6)WC3_C6環烷基。 、、；另貞更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式IA1、；fA9 τλο f ί 、ΙΑ3、ΙΑ4、ΙΑ5、ΙΒ1、ΙΒ2、ΙΒ3、ΙΒ4 或IB5化合物，发巾γ^ > ” τ Α 為 〇，q= ί，υ 為 s，且 r5 為 q -c6 烷基In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula ffi wherein X is S, q = 1, ¥ is 8, and the core is 夂 alkyl, (CHR6) WC3- C6 cycloalkyl, (CHR6) WCH2C3-C6 cycloalkyl or CH2(CHR6)w C3-c6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IB wherein χ is s, q = i ' γ is s, and ^ is cr6=ch-c3-c6 cycloalkyl , ch=cr6-c3-c^alkyl, (CHR6)wC5_C6 cyclodecyl, ch2(chr6)wc5_C6 cycloaliphatic, C2_C6 alkenyl or c2_c6 block. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IB, wherein χ is s, q = i, γ is s, and the heart is An, (CHR6) wAri, CH2 (CHR6) wAri or (CHR6) wCH2Ari. π is a more specific 1,ΙΑ2,ΙΑ3,ΙΑ4 or 1Β5 compound, wherein X is 0, q or (CHR6)WC3-C6 cycloalkyl. IA5, IB1, ffi2, IB3, IB41, Y are ο, and I is c丨-C6 alkane in another more specific sub-specific embodiment, the present invention provides or intends to enclose IA1, IA2 IA3, IA4, IA5, lm, lm, e.g., iB4 or ΪΒ5 compound, wherein x is s, a = i, γ or Q p D 〇 八 入 into horse s, ql, y is s, and r5aCi_C6 alkyl 132252 - 27- 200914452 or (CHR6) WCVC6 cycloalkyl. In a specific embodiment of the invention, the present invention provides or intends to cover a compound of the formula IA1 'ΤΛ, 1Α3, ΙΑ4, ΙΑ5, ΙΒ1, ΙΒ2, ΙΒ3, ΙΒ4 or IB5, and the complex is "8,9" =: 1, ¥ is 0, and 115 is (: 1-(: 6 alkyl or (CHR6) WC3_C6 cycloalkyl. , ,; and further specific subgenus. In particular embodiments, the invention provides or is intended to cover Formula IA1;;fA9 τλο f ί,ΙΑ3,ΙΑ4,ΙΑ5,ΙΒ1,ΙΒ2,ΙΒ3,ΙΒ4 or IB5 compound, hair towel γ^ > ” τ Α is 〇, q= ί, υ is s, and r5 is q -c6 alkyl

或（CHR6)wC3-C6環烷基 D 、、；貞更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、ΤΔ·3 ΤΛ 1Α3、ΙΑ4、ΙΑ5、ΙΒ1、、ffi3、ΙΒ4 或化合物，立中χ我 八τ λ為〇，q =零，且r5為q -c6烷基或 (CHR6 )w c3 -c6 環烷基。 〃:又更特殊亞屬具體實施例中，本發明係提供或意欲涵 蓋式 IA1、IA2、IA3、IM、ΙΑ5、ΐβΐ、脱脱、脱或脱 产勿八中X為〇，q =零，且R5為C5-C6烷基、CH2-C5-C6 %烷基、CH2CH2_N_四氫吡咯基或CH2CH2-C5-CVf烷基。 立；另項又更特殊亞屬具體實施例中，本發明係提供或 w 奴涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、ΓΒ2、IB3、IB4 或B5化合物，其中x為〇，q = 1，Y為〇，且R5為C5 -C6烷基、 CH2 cs -C6環烷基或ch2 ch2 -N-四氫吡咯基或CH2 CH2 -C5 -C6環 烷基。 於另—項更特殊亞屬具體實施例中’本發明係提供或意 奴 /函盖式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、IB3、IB4 132252 -28 - 200914452 或IB5化合物’其中&為鹵素；&為η、鹵素或Cl_c4烷基； X為〇 ;且R5為Cl_C6烷基、（CHR^q-Q環烷基、 (CHR6 )w CH2 C3 -Q 環烷基或 CH2 (CHR6 )w C3 -C6 環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、ffi2、IB3、；[B4Or (CHR6) wC3-C6 cycloalkyl D, , 贞 more specific subgenus, in particular embodiments, the invention provides or intends to encompass the formula IA1, IA2, ΤΔ·3 ΤΛ 1Α3, ΙΑ4, ΙΑ5, ΙΒ1, ffi3 , ΙΒ4 or compound, Lizhong χ I 八τ λ is 〇, q = zero, and r5 is q-c6 alkyl or (CHR6)w c3 -c6 cycloalkyl. 〃: In a more specific sub-specific embodiment, the present invention provides or intends to cover the formula IA1, IA2, IA3, IM, ΙΑ5, ΐβΐ, detachment, detachment or detachment, and X is 〇, q = zero, and R5 is C5-C6 alkyl, CH2-C5-C6% alkyl, CH2CH2_N_tetrahydropyrrolyl or CH2CH2-C5-CVf alkyl. In another embodiment of the invention, the invention provides or exemplifies a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, ΓΒ2, IB3, IB4 or B5, wherein x is 〇, q = 1, Y is 〇, and R5 is C5-C6 alkyl, CH2 cs-C6 cycloalkyl or ch2 ch2-N-tetrahydropyrrolyl or CH2CH2-C5-C6 cycloalkyl. In a further specific sub-specific embodiment, 'the invention provides or is intended to cover or cover IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 132252-28-200914452 or IB5 compound' Wherein & is halogen; & is η, halogen or Cl_c4 alkyl; X is hydrazine; and R5 is Cl_C6 alkyl, (CHR^qQ cycloalkyl, (CHR6)w CH2 C3 -Q cycloalkyl or CH2 ( CHR6)w C3 -C6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass formulas IA1, IA2, IA3, IA4, IA5, IB1, ffi2, IB3,; [B4

或K5化合物，其中心為鹵素或鹵甲基；r2為η、鹵素或^ _Q 烧基；X為〇 ;且Rs為Ci_Q烷基、（CHR6)w(VC6環烷基、 (CHR6 )w CH2 C3 _c6 環烷基或 CH2 (CHR6 )w c3 -c6 環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、ro2、IB3、IB4 或化&物’其中1^為鹵素或鹵甲基；r2為η、鹵素或q -C4 烷基，R’為鹵素、曱基或鹵甲基；X為〇;且心為^—^烷基、 (c®6 )w c3 -c6 環烷基、（CHR6 )W ch2 c3 _c6 環烷基或 Ch2 (CHR6 )w C3-C6環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 "人’函盍式 IA1、IA2、IA3、IA4、IA5、；[B1、m2、IB3、IB4 或1化合物，其中χ為〇叫=零，且^為。-^烷基、Ch2CH2_ 環戊基或下文基團之一： ch2chOr a K5 compound having a halogen or halomethyl group; r2 is η, halogen or ^ _Q alkyl; X is hydrazine; and Rs is Ci_Q alkyl, (CHR6)w (VC6 cycloalkyl, (CHR6)w CH2 C3 _c6 cycloalkyl or CH2(CHR6)w c3 -c6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass formulas IA1, IA2, IA3, IA4, IA5, IB1 , ro2, IB3, IB4 or chemical & ''1' is halogen or halomethyl; r2 is η, halogen or q-C4 alkyl, R' is halogen, fluorenyl or halomethyl; X is hydrazine; And the heart is ^-^alkyl, (c®6)w c3 -c6 cycloalkyl, (CHR6)W ch2 c3 _c6 cycloalkyl or Ch2 (CHR6)w C3-C6 cycloalkyl. In particular embodiments of the invention, the invention provides or intends to mean IA1, IA2, IA3, IA4, IA5, [B1, m2, IB3, IB4 or 1 compound, wherein χ is 〇 = = Zero, and ^ is .-^alkyl, Ch2CH2_cyclopentyl or one of the following groups: ch2ch

ch2chCh2ch

Η、Oh,

〇〇

ch2ch2~~Ch2ch2~~

NH ch2chNH ch2ch

132252 -29- 200914452 〇 〇Η2〇Η2-^ΝΗ CH2CH2&quot;^X0 0Η2^η2-&lt;^ΝΗ ch2ch2-&lt;^] 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、ffi3、IB4 或IB5化合物，其中心為鹵素或鹵甲基；R2為Η、鹵素或q -C4 烷基；X為Ο;且115為上文基團之一。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 ΙΑ1、ΙΑ2、ΙΑ3、ΙΑ4、ΙΑ5、ΙΒ1、ΙΒ2、ΙΒ3、ΙΒ4 ί 或ΙΒ5化合物，其中X為S，q =零，且R5為Ci -C6烷基或 (CHR6)WC3-Cpf、烷基。 於另一項亞屬具體實施例中，本發明係提供或意欲涵蓋 式 IA1、IA2、IA3、IA4、IA5、ffil、ffi2、IB3、IB4 或 ffi5 化 合物，其中 &amp; 為 Η、CN、鹵素、CH2CN、OH、N02、CH2F、 CHF2、CF3、CF2CF3、CVQ 烷基或 CbCOCrQ 烷基。 於另一項亞屬具體實施例中，本發明係提供或意欲涵蓋 式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、IB3、EB4 或 IB5 化 I 合物，其中 R,為 ¢:(=0)(^ -C6 烷基、NHC^COC! -C6 烷基、 C(=0)N(CH3)2、C(=0)N(R)2、CpCONH-CVQ烷基、（：(=0)0(：】-C6 烷基或0(:(=0)(^ -c6烷基。 於另一項亞屬具體實施例中，本發明係提供或意欲涵蓋 式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、IB3、IB4 或 IB5 化 合物，其中心為OC! -C6烷基、SCi -c6烷基、c3 -c6環烷基、 (CH2 )m C3 -C6 環烷基、C3 -C6 環烯基、（CH2 )m c3 -c6 環烯基、c2 -c6 烯基或c2-c6炔基。 132252 30· 200914452 於另一項亞屬具體實施例中，本發明係提供或意欲涵蓋 式 IA1、IA2、IA3、IA4、IA5、EB1、IB2、IB3、IB4 或 IB5 化 合物，其中心為苯基、吡啶基、吡咯基、（CH2)m吡畊基、（CH2)m 咪唑基、（CH2)m崎唑基、（CH2)m異噚唑基、（CH2)m^唑基、 (CH2 )m吡啶基、（CH2 )m異嘧唾基、（CH2 )m苯基、（CH2 )m吡咯 基或啶基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、IB3、IB4 或IB5化合物，其中&amp;為(:(=0)(^ -C6烷基、NHCtCOC! -C6烷基、 C(=0)N(CH3)2、C(=0)N(Et)2、CpCONH-CVQ 烷基、CpOpq-Q 烷基或0(:(=0)(^ -C6烷基，且R5為C5 -C6烷基或CH2 -c3 -c6環烷 基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、ΓΒ3、ffi4 或IB5化合物，其中烷基、SCVQ烷基、（：3-(：6環 烷基、（CH2)mC3-C6環烷基、C3-C6環烯基、（CH2)mC3-C6環烯 基、C2-C6烯基或C2-C6炔基，且R5為C5-C6烷基或CH2-C3-C6 環烧基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、IB2、IB3、IB4 或IB5化合物，其中&amp;為苯基、吡啶基、吡咯基、（CH2)„^ 嗤基、（(:氏:^吡畊基、（CH2)m哼嗤基、（CH2)m異噚嗤基、（CH2)m 嘍唑基、（CH2)m異嘧唑基、（CH2)m苯基、（CHJ，!：咯基、（CH2)m 吡啶基或（CH2)m嘧啶基，且R5為C5-C6烷基或CH2-C3-C6環烷 132252 -31 - 200914452 基。 於項更特殊亞屬具體實施例中，本發明係提供或意欲 涵盍任何式IA1-IA5化合物，其中χ為〇，q=1，丫為〇，且 &amp;為Ari4CH2-Ari，其中Αη為未經取代之苯基、經單取代之 苯基、未經取代之吡啶基或未經取代之吡咯基。 於另工員更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋任何式ΙΑ1-ΙΑ5化合物，其中X為〇, 9=零，且心為 Αη或CH2_Ari ’其中Αη為未經取代之苯基、經單取代之苯 基、未經取代之吡啶基或未經取代之吡咯基。 於另-項亞屬具體實施例中，本發明係提供或意欲涵蓋 式1Α或1Β化合物，其中Ri與I係形成稠合苯基，Χ為〇，q = 1，γ為〇，且心為^—^烷基或（CHR6)wC3_C6環烷基。 於另一項亞屬具體實施例中，本發明係提供或意欲涵蓋 式IA或IB化a物’其中尺丨與〜係开》成稠合峨咬基，X為〇， q 1，Y為〇，且R5為C丨-C6烷基或（(：^〇16)*(：3-(：6環烷基。 於另一項亞屬具體實施例中’本發明係提供或意欲涵蓋 式 IA1、IA2、IA3、IA4、IA5、lm、Im、m3、脱或脱化 &amp;物其中R,為素、q -Q烧基、單-函基Ci 烧基、CN、 二-鹵基 CVC6 烷基、cf3、CN 或 aCi_c6 烷基，且 R^C5_C6 烷基或CH2 -C3 -c6環烷基。 於另-項更特殊亞屬具體實施例中’本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、、IB3、脱 或IB5化合物’其中Rl為函素、氰基、％或甲氧基，r^h 或甲基，R，為Η、_素或甲基，且仏為C5_Q烧基或CH2 _C3_C6 132252 -32· 200914452 環烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式1、IA2、IA3、IA4、IA5、IB1、ιΒ2、IB3、IB4 或IB5化合物，其中R,為鹵素、CF3或q _C3烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、IB1、、IB3、IB4 或ffi5化合物，其中心為鹵素；&amp;為H或曱基，R，為H、鹵 素或曱基；且R5為CVQ烷基或CH2_C5_Cpt烷基。 於另一項更特殊亞屬具體實施例中，本發明係提供或意 欲涵蓋式 IA1、IA2、IA3、IA4、IA5、lm、m2、Ιβ3、ib4 或IB5化合物，其中Ri為鹵素；為H或甲基，1^為1^、鹵 素或甲基’且Rs為CH2 -C4 -烧基或CH: -C5 -烧基。 於另一項亞屬具體實施例中，本發明係提供式“匕合物， 其中R】或Rs為CHaAr!或，其中Αη為苯基、吡啶 基、吡咯基、咪唑基、呤唑基或嘧唑基。 於另一項亞屬具體實施例中，本發明係提供式合物， 其中R〗與％係形成吡咯并、咪唑并、噚唑并或嘧唑并。 於另一項亞屬具體實施例中，本發明係提供式〗化合物， 其中R】或R5為CH2 Ar】或CH2 CH2 -Ar!，其巾Αη為異》号。坐基或 異嘧唑基。 於另一項亞屬具體實施例中，本發明係提供式〗化合物， 其中Rl或R5為CH2 Ari或ch2CH2，，其中-為心林基或異 0奎P林基。 於另-項亞屬具體實施例中，本發明係提供式工化合物， 132252 -33- 200914452 其中R!或Rs為CH2Ari或C^CIVAr!，其中Ari為嘧啶基或嘌 呤基。 於另一項亞屬具體實施例中，本發明係提供式I化合物， 其中R!或Rs為CH2 Ari或，其中Ari為吲哚基、異 丨嗓基或苯并咪。坐基。 於一項更特殊具體實施例中，本發明係提供式I化合物， 其中R丨或Rs為CH2 Ar丨或CH2 CH2 -Ar!，其中Ar丨為_笨基。 於另一項更特殊具體實施例中，本發明係提供式j化合 物，其中K或R5為CH2Ari或CH2CH2_Ari，其中炝丨為二_笨 基或二i吡啶基。 於另一項更特殊具體實施例中，本發明係提供或意欲涵 盍式I化合物，其中Ari為單_或二_鹵嘍吩基、單-或二-函呋 喃基、單-或二-齒苯并嘍吩基或單-或二_商苯并呋喃基。 於另一項更特殊具體實施例中，本發明係提供或意欲涵 蓋式I化合物，其中心或尺5為CH2Ari或CH2CH2_Ari，其中^ 為鄰-、間-或對-二甲苯基或鄰_、間_或對-對甲氧苯基。 於另-項更特殊具體實施例中，本發明係提供或意欲涵 蓋式I化合物，其中R]或為CH2 Ari或CH2CH2_Ari，其中^ 為間-或對-氱基笨基或間-或對_氰基曱基苯基。 於另一項更特殊具體實施例中，本發明係提供式丨化合 物’其中&amp;或R5為CH2Ari或CH2CH2_Ari，其中Μ為C2_CA 基苯基。 於另一項更特殊具體實施例中，本發明係提供式丨化合 物”中 I 或 R5 為 Ci^Ar,或 Ct^CHrAr!，其中 ΑΓι 為 3,5-二氯 132252 •34- 200914452 苯基或3,5-二氟苯基。 於一項更特殊具體實施例中’本發明係提供式I化合物， 其中 R!或 R5 為 Αη 、 （CHR^Ar! 、 CHdCHR^Ar!或 (CHR^XvCI^Ari，其中Aq為苯基或峨π定基，％與r4為η或 q -C6娱:基、未經取代或被一或兩個選自〇Η、〇Me之基團取 代；Ri為CN、CH2 CN或鹵素；q為1;且X與γ均為〇。 於另一項亞屬具體實施例中，本發明係提供式j化合物， 其中 R5 為 Αη、（CHR6)wAr丨、CHdCHR^Ar!或（CHRdwCP^Aq， 其中Aq為笨基或！τ比咬基’ r〗為ρ、ch2F、CHF2、CF3或 CF2CF3 ’ q為1，且X與γ均為〇。 於一項更特殊具體實施例中，本發明係提供式丨化合物， 其中 &amp; 或 R5 為 Αη 、 （CHR6)wAri 、 CH2(CHR6)wAri 或 (CHRJwCI^Ar! ’其中Αη為苯基或吡啶基，心為〇(^_(：6烷基 或(：(=0)(：〗-C6烷基，q為1，且X與γ均為〇。 於一項更特殊具體實施例中，本發明係提供式〗化合物， 其中 Ri 或 R5 為 Αη、（CHR6)wAri、CHdCHR^wAq 或 (CHR6)WCH2 Αη ’其中Ar!為苯基或峨啶基，&amp;為c(=〇)〇Ci ^ 烷基或〇c(=0)ci-c6烷基，q為1，且X與Y均為0。 於一項更特殊具體實施例中，本發明係提供式合物， 其中 R5 為 Aq、（CHR6)wAri、CHWCHR^ArAfHR^wO^Ar^ ’ 其中Αη為笨基或㈣基’ Ri^2_C6烯基或快基，q為 1 ’且X與Y均為〇。 於一項更特殊具體實施例中，本發明係提供式工化合物， 其中-中 R5 為 Ar! 、（CHR^wAr! 、CH2(CHR6)wAri 或 132252 -35- 200914452 (CHR6)WCH2 Ar] ’ Ari為苯基或峨咬基，Ri為sc「c6烧基，c 為1 ’且X與Y均為0。 於一項更特殊具體實施例中，本發明係提供式Hb合物， ^ tR5^Ari &gt; (CHR6)wAri ^ CH2 (CHR6 )w ΑΓι ic (CHR6 )w CH2 Αη , 其中Αη為笨基或吡啶基，烷基，132252 -29- 200914452 〇〇Η2〇Η2-^ΝΗ CH2CH2&quot;^X0 0Η2^η2-&lt;^ΝΗ ch2ch2-&lt;^] In another more specific sub-specific embodiment, the present invention provides or intends a compound of the formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, ffi3, IB4 or IB5 having a center of halogen or halomethyl; R2 is deuterium, halogen or q-C4 alkyl; X is deuterium; Is one of the above groups. In another more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula 1, ΙΑ2, ΙΑ3, ΙΑ4, ΙΑ5, ΙΒ1, ΙΒ2, ΙΒ3, ΙΒ4 ί or ΙΒ5, where X is S, q = Zero, and R5 is Ci-C6 alkyl or (CHR6) WC3-Cpf, alkyl. In another sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA1, IA2, IA3, IA4, IA5, ffil, ffi2, IB3, IB4 or ffi5, wherein &amp; is Η, CN, halogen, CH2CN, OH, N02, CH2F, CHF2, CF3, CF2CF3, CVQ alkyl or CbCOCrQ alkyl. In another sub-specific embodiment, the invention provides or is intended to encompass a formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, EB4 or IB5, wherein R, is ¢: ( =0) (^ -C6 alkyl, NHC^COC! -C6 alkyl, C(=0)N(CH3)2, C(=0)N(R)2, CpCONH-CVQ alkyl, (:( =0) 0 (:) - C6 alkyl or 0 (: (=0) (^ - c6 alkyl. In another sub-specific embodiment, the invention provides or intends to encompass the formula IA1, IA2, IA3 , IA4, IA5, IB1, IB2, IB3, IB4 or IB5 compound, centered at OC! -C6 alkyl, SCi-c6 alkyl, c3 -c6 cycloalkyl, (CH2)m C3 -C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)m c3 -c6 cycloalkenyl, c2-c6 alkenyl or c2-c6 alkynyl. 132252 30· 200914452 In another sub-specific embodiment, the invention provides or It is intended to cover compounds of formula IA1, IA2, IA3, IA4, IA5, EB1, IB2, IB3, IB4 or IB5, centered on phenyl, pyridyl, pyrrolyl, (CH2)m pyridinyl, (CH2)m imidazolyl , (CH2)m-oxazolyl, (CH2)m isoxazolyl, (CH2)m^azolyl, (CH2)mpyridyl, (CH2)misopyranyl, (CH2 m)phenyl, (CH2)mpyrrolyl or pyridyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass the formulas IA1, IA2, IA3, IA4, IA5, IB1, IB2. IB3, IB4 or IB5 compound, wherein &amp; is (:(=0)(^ -C6 alkyl, NHCtCOC! -C6 alkyl, C(=0)N(CH3)2, C(=0)N(Et 2) CpCONH-CVQ alkyl, CpOpq-Q alkyl or 0 (:(=0)(^-C6 alkyl, and R5 is C5-C6 alkyl or CH2-c3-c6 cycloalkyl. In a more specific sub-specific embodiment, the invention provides or intends to encompass a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, ΓΒ3, ffi4 or IB5, wherein alkyl, SCVQ alkyl, (:3 -(: 6 cycloalkyl, (CH2)mC3-C6 cycloalkyl, C3-C6 cycloalkenyl, (CH2)mC3-C6 cycloalkenyl, C2-C6 alkenyl or C2-C6 alkynyl, and R5 is C5-C6 alkyl or CH2-C3-C6 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass formulas IA1, IA2, IA3, IA4, IA5, IB1, IB2. IB3, IB4 or IB5 compound, wherein &amp; is phenyl, pyridyl, pyrrolyl, (CH2) ^ 嗤 、, ((:: 吡 吡 耕, (CH2) m哼嗤 group, (CH2)m isoindolyl, (CH2)m carbazolyl, (CH2)misopyrazolyl, (CH2)mphenyl, (CHJ, !: yl, (CH2)m Pyridyl or (CH2)mpyrimidinyl, and R5 is C5-C6 alkyl or CH2-C3-C6 cycloalkane 132252-31 - 200914452. In a more specific sub-specific embodiment, the invention provides or intends to encompass any compound of formula IA1-IA5 wherein χ is 〇, q=1, 丫 is 〇, and &amp; is Ari4CH2-Ari, wherein Αη is Unsubstituted phenyl, monosubstituted phenyl, unsubstituted pyridyl or unsubstituted pyrrolyl. In a more specific sub-specific embodiment of the worker, the invention provides or intends to encompass any compound of formula ΙΑ1-ΙΑ5, wherein X is 〇, 9=zero, and the core is Αη or CH2_Ari 'where Αη is unsubstituted benzene A monosubstituted phenyl group, an unsubstituted pyridyl group or an unsubstituted pyrrolyl group. In a specific embodiment of the sub-genus, the invention provides or intends to encompass a compound of formula 1 or 1 ,, wherein Ri and I form a fused phenyl group, Χ is 〇, q = 1, γ is 〇, and the heart is ^—^alkyl or (CHR6)wC3_C6 cycloalkyl. In another sub-specific embodiment, the present invention provides or intends to encompass a formula IA or a IB-formed substance in which a scorpion and a stalk are fused to a bite group, X is 〇, q 1, Y is 〇, and R5 is C丨-C6 alkyl or ((:^〇16)*(:3-(:6-cycloalkyl). In another sub-specific embodiment, the invention provides or intends to encompass IA1, IA2, IA3, IA4, IA5, lm, Im, m3, de- or de-synthesis &amp; R, is a prime, q-Q alkyl, mono-functional Ci alkyl, CN, di-halogen CVC6 Alkyl, cf3, CN or aCi_c6 alkyl, and R^C5_C6 alkyl or CH2-C3-c6 cycloalkyl. In a further specific sub-general embodiment, the invention provides or intends to encompass Formula IA1 IA2, IA3, IA4, IA5, IB1, IB3, de- or IB5 compound 'where R1 is a lignin, cyano, % or methoxy, r^h or methyl, R, Η, _ or methyl And 仏 is C5_Q alkyl or CH2_C3_C6 132252 -32· 200914452 cycloalkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass Formula 1, IA2, IA3, IA4, IA5, IB1, ιΒ2, IB3, IB4 or IB5 compound, Wherein R is halogen, CF3 or q-C3 alkyl. In another more specific sub-specific embodiment, the invention provides or intends to encompass formulas IA1, IA2, IA3, IA4, IA5, IB1, IB3, IB4 Or a ffi5 compound, the center of which is a halogen; &amp; is H or a fluorenyl group, R is H, a halogen or a fluorenyl group; and R5 is a CVQ alkyl group or a CH2_C5_Cpt alkyl group. In another more specific sub-specific embodiment The invention provides or intends to encompass a compound of formula IA1, IA2, IA3, IA4, IA5, lm, m2, Ιβ3, ib4 or IB5, wherein Ri is halogen; H or methyl, 1^ is 1^, halogen or A The base 'and Rs is CH 2 -C 4 -alkyl or CH: -C5 -alkyl. In another sub-specific embodiment, the invention provides the formula "chelate, wherein R" or Rs is CHAAr! or Wherein Αη is phenyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl or pyrazolyl. In another sub-specific embodiment, the present invention provides a formula wherein R and % are formed Pyrrolo, imidazo, oxazolo or pyrazolo. In another sub-specific embodiment, the invention provides a compound of the formula wherein R] or R5 is CH 2 Ar] or CH2 CH2 -Ar!, the Αη is a different number. Sitylene or isopyrazolyl. In another sub-specific embodiment, the present invention provides a compound of the formula wherein R1 or R5 is CH2 Ari or ch2CH2, where - is a cardinyl or an iso-ou P-lin. In a further embodiment of the sub-genus, the invention provides a compound of the formula, 132252-33-200914452 wherein R! or Rs is CH2Ari or C^CIVAr!, wherein Ari is pyrimidinyl or indolyl. In another sub-specific embodiment, the invention provides a compound of formula I, wherein R! or Rs is CH2Ari or wherein Ari is indolyl, isoindolyl or benzimid. Sitting on the base. In a more particular embodiment, the invention provides a compound of formula I, wherein R丨 or Rs is CH2Ar丨 or CH2CH2-Ar!, wherein Ar丨 is _styl. In another more specific embodiment, the invention provides a compound of formula j wherein K or R5 is CH2Ari or CH2CH2_Ari, wherein 炝丨 is a di-phenyl or di-ipyridyl. In another more specific embodiment, the invention provides or intends to encompass a compound of formula I, wherein Ari is mono- or di-haloquinolyl, mono- or di-f-furyl, mono- or di- A benzobenzophenyl group or a mono- or di-complex benzofuranyl group. In another more specific embodiment, the invention provides or intends to encompass a compound of formula I, the center or the rule 5 of which is CH2Ari or CH2CH2_Ari, wherein ^ is o-, m- or p-xylyl or o-, Between _ or p-p-methoxyphenyl. In a further particular embodiment, the invention provides or intends to encompass a compound of formula I, wherein R] is either CH2 Ari or CH2CH2_Ari, wherein ^ is m- or p-mercapto or m- or p- Cyanodecylphenyl. In another more specific embodiment, the invention provides a compound of the formula </RTI> wherein &amp; or R5 is CH2Ari or CH2CH2_Ari, wherein hydrazine is a C2_CA-phenyl group. In another more specific embodiment, the invention provides a compound of the formula "I or R5 is Ci^Ar, or Ct^CHrAr!, wherein ΑΓι is 3,5-dichloro 132252 • 34- 200914452 phenyl Or 3,5-difluorophenyl. In a more specific embodiment, the invention provides a compound of formula I, wherein R! or R5 is Αη, (CHR^Ar!, CHdCHR^Ar! or (CHR^ XvCI^Ari, wherein Aq is a phenyl or 峨π group, and % and r4 are η or q-C6, which are unsubstituted or substituted by one or two groups selected from the group consisting of ruthenium and osmium; Ri is CN, CH2 CN or halogen; q is 1; and X and γ are both 〇. In another sub-specific embodiment, the invention provides a compound of formula j, wherein R5 is Αη, (CHR6)wAr丨, CHdCHR ^Ar! or (CHRdwCP^Aq, where Aq is stupid or !τ is more than bite base r is ρ, ch2F, CHF2, CF3 or CF2CF3 'q is 1, and X and γ are both 〇. In a particular embodiment, the present invention provides a hydrazine compound wherein &amp; or R5 is Αη, (CHR6)wAri, CH2(CHR6)wAri or (CHRJwCI^Ar! 'where Αη is phenyl or pyridyl, 〇(^_( 6 alkyl or (: (=0) (: - C6 alkyl, q is 1, and X and γ are both 〇. In a more specific embodiment, the invention provides a compound of the formula, wherein Ri Or R5 is Αη, (CHR6)wAri, CHdCHR^wAq or (CHR6)WCH2 Αη 'where Ar! is phenyl or acridinyl, &amp; is c(=〇)〇Ci ^ alkyl or 〇c(=0 Ci-c6 alkyl, q is 1, and X and Y are both 0. In a more specific embodiment, the invention provides a formula wherein R5 is Aq, (CHR6) wAri, CHWCHR^ArAfHR ^wO^Ar^ ' where Αη is a stupid or (d)yl ' Ri^2_C6 alkenyl or a fast radical, q is 1 ' and X and Y are both 〇. In a more specific embodiment, the invention provides a compound of the formula, wherein -R5 is Ar!, (CHR^wAr!, CH2(CHR6)wAri or 132252-35-200914452 (CHR6)WCH2 Ar] 'Ari is a phenyl or a thiol base, and Ri is a sc "c6 The alkyl group, c is 1 ' and both X and Y are 0. In a more specific embodiment, the invention provides a compound of formula Hb, ^ tR5^Ari &gt; (CHR6) wAri ^ CH2 (CHR6)w ΑΓι ic (CHR6 )w CH2 Αη , where Αη is a stupid or pyridyl group, an alkyl group,

Cj -C6烷基，q為零，且χ為〇。 於一項更特殊具體實施例中，本發明係提供式〗化合物， 其中 ΜΑη、（CHR^Ar!、CHdCHR^Aq 或（CHR6)wCH2Ari， 其中私為苯基或吡啶基；&amp;與心為11或（：1_^烷基；&amp;為 C!-C6烷基；q為i ;且又為〇。 於項更特殊具體實施例中，本發明係提供式j化合物， 其中 R5 為 Αη、（CHR6)wAri、CH2(CHR6)wAri 或（CHR6)wCH2 Ari， 其中Ar!為苯基或吡啶基，&amp;與仏為Η或c厂^烷基，心為 CN、CH2CN或鹵素，£1為1 , γ為〇 ’且乂為〇。 ' 於另一項具體實施例中，本發明係提供式j化合物，其中 R5 為 Αη、（CHR6)wAri、CH2(CHR6)wAri 或（CHR6)wCH2Ari，其 中炝1為嘍吩基、呋喃基、苯并嘍吩基或苯并呋喃基；r3與 尺4係獨立為Η、甲基或乙基；且心為Ci_Q烷基^ (CHR6 )w C3 -C6 環烧基。 於另一項具體實施例中’本發明係提供式I化合物，其中 R5 為 ΑΓι、（CHR6)wAri、CH2(CHR6)wAri 或（CHR6)wCH2Ar〗，其 中Ari為吡咯基、咪唑基、P号唑基或噻唑基；I與比係獨立 為H、曱基或乙基；且化為心七6烷基或（chr6)wc3-c6環烷基。 於另一項具體實施例中，本發明係提供式I化合物，其中 132252 -36- 200914452 R5 為 Αη、（CHR6)wAri、CH2(CHR6)wAri 或（CHR6)wCH2Ari，其 中Ar〗為異P号唑基或異嘧唑基；&amp;與R4係獨立為Η、曱基或 乙基；且Rs為CpC6烷基或（CHR6)WC3-C6環烷基。 於另一項具體實施例中，本發明係提供式I化合物，其中 R5為C〗-Q烷基，其中烷基係被一或兩個基團取代，取代基 獨立選自 OH、〇Me、OEt、F、CF3、C1 或 CN。Cj-C6 alkyl, q is zero, and χ is 〇. In a more specific embodiment, the invention provides a compound of the formula wherein ΜΑη, (CHR^Ar!, CHdCHR^Aq or (CHR6)wCH2Ari, wherein the phenyl or pyridyl group is private; &amp; 11 or (:1_^alkyl; &amp; is C!-C6 alkyl; q is i; and is also 〇. In a more specific embodiment, the invention provides a compound of formula j, wherein R5 is Αη, (CHR6) wAri, CH2(CHR6)wAri or (CHR6)wCH2 Ari, where Ar! is phenyl or pyridyl, &amp; and 仏 is Η or c ^ alkyl, heart is CN, CH2CN or halogen, £1 Is 1 and γ is 〇' and 乂 is 〇. In another specific embodiment, the invention provides a compound of formula j, wherein R5 is Αη, (CHR6)wAri, CH2(CHR6)wAri or (CHR6)wCH2Ari Wherein 炝1 is an anthracene group, a furyl group, a benzoquinone group or a benzofuranyl group; and the r3 and the rule 4 are independently a hydrazine, a methyl group or an ethyl group; and the core is a Ci_Q alkyl group (CHR6)w C3 -C6 cycloalkyl. In another embodiment, the invention provides a compound of formula I, wherein R5 is ΑΓι, (CHR6) wAri, CH2(CHR6)wAri or (CHR6)wCH2Ar, wherein Ari is pyrrole a group, an imidazolyl group, an oxazolyl group or a thiazolyl group; I is independently H, a fluorenyl or an ethyl group; and is converted to a heart of a hepta-6 or a (chr6)wc3-c6 cycloalkyl group. In a particular embodiment, the invention provides a compound of formula I, wherein 132252 - 36 - 200914452 R5 is Αη, (CHR6) wAri, CH2(CHR6)wAri or (CHR6)wCH2Ari, wherein Ar is an iso-P azole group or different Pyrazolyl; &amp; R4 is independently oxime, fluorenyl or ethyl; and Rs is CpC6 alkyl or (CHR6) WC3-C6 cycloalkyl. In another embodiment, the invention provides Compound I wherein R5 is C&apos;-Q alkyl wherein the alkyl group is substituted by one or two groups independently selected from OH, 〇Me, OEt, F, CF3, C1 or CN.

於另一項具體實施例中，本發明係提供式I化合物，其中 R5為（CHR6 )w C3 -c6環烧基，其中w為1或2，且r6為Η或曱基， 及其中 ％ 烧基係被 Me、OH、OMe、OEt、F、CF3、C1 或 CN 取代。 於一項更特殊具體實施例中’本發明係提供式I化合物， 其中&amp;為（CH：2 )w -C：5 -Q環烷基或（CH2 )w -C5 -C6雜環烷基。 於另一項具體實施例中’本發明係提供式I化合物，其中 Rs為CH=CH-C3 -C：6環烷基或雜環烷基，其中碳_碳雙鍵具有E 組態。 於另一項具體實施例中，本發明係提供式】化合物，其中 Rs為CH=CH-C3 -C6環烷基或雜環烷基，其中碳-碳雙鍵具有z 組態。 於另一項具體實施例中，本發明係提供式j化合物，其中 Rs為C^-CHCH-q-C6環烷基或雜環烷基，其中碳-碳雙鍵具 有E組態。 於另一項具體實施例中，本發明係提供式j化合物，其中 &amp;為CH2CH=CH-C3-C6環烷基或雜環烷基，其中碳-碳雙鍵具 有Z組態。 132252 -37. 200914452 於另一項具體實施例中’本發明係提供式i化合物，其中 R_5為CH=CH-CH2 -C：3 -Q環炫基或雜環烧基，其中碳-碳雙鍵具 有E組態。 於另一項具體實施例中，本發明係提供式I化合物，其中 心為CH=CH-CH2-(：3-C6環烷基或雜環烷基，其中碳_碳雙鍵具 有Z組態。 於另一項更特殊具體實施例中，本發明係提供式丨化合 物其中R5為（chr0 )w C：3 -C；6環院基或雜環烧基，其中環烧基 或雜環烷基係經單取代。 於另一項具體實施例中，本發明係提供式I化合物，其中 尺5為CH=CH-CH2 -C：3 -C：6環烷基或雜環烷基或CH=CH_C3 %環烷 基或雜環烷基，其中環烷基或雜環烷基係經單取代。 於另一項具體實施例中’本發明係提供式I化合物，其中 化為仏-仏烷基。 於另一項具體實施例中，本發明係提供式J化合物，其中 q為零’且Rs為CHrC4·烧基或CH2-C5-烧基。 於另一項具體實施例中，本發明係提供式J化合物，其中 R5為C2 -C6炔基。 於另一項具體實施例中，本發明係提供式J化合物，其中 R5為C2-C6烯基。 於一項更特殊具體實施例中，本發明係提供式IA1、IA2、 IA3、IA4或IA5化合物，其中X為〇，r2、R，及為H，且q = 零。 於另一項具體實施例中，本發明係提供式IB1、IB2、m3、 132252 -38- 200914452 IB4或IB5化合物，其中χ為〇，&amp;、R，及r^h，且^零。 於一項更特殊具體實施例中，本發明係提供式以丨、IA2、 IA3 ΙΑ4或1A5化合物，其中X為〇，r2與R，為H , &amp;與心 為甲基或甲氧基，且q =零。 於另一項具體實施例中’本發明係提供式IB1、、iB3、 IB4或IB5化合物，其中χ為〇，R^R，為H ,心與^為曱基 或甲氧基，且q =零。In another embodiment, the invention provides a compound of formula I, wherein R5 is (CHR6)w C3-c6 cycloalkyl, wherein w is 1 or 2, and r6 is hydrazine or fluorenyl, and wherein The base system is replaced by Me, OH, OMe, OEt, F, CF3, C1 or CN. In a more specific embodiment, the invention provides a compound of formula I, wherein &amp; is &lt;CH:2)w-C:5-Q cycloalkyl or (CH2)w-C5-C6 heterocycloalkyl . In another embodiment, the invention provides a compound of formula I, wherein Rs is CH=CH-C3 -C: 6 cycloalkyl or heterocycloalkyl, wherein the carbon-carbon double bond has an E configuration. In another embodiment, the invention provides a compound of formula wherein Rs is CH=CH-C3-C6 cycloalkyl or heterocycloalkyl, wherein the carbon-carbon double bond has a z configuration. In another embodiment, the invention provides a compound of formula j, wherein Rs is C^-CHCH-q-C6 cycloalkyl or heterocycloalkyl, wherein the carbon-carbon double bond has an E configuration. In another embodiment, the invention provides a compound of formula j, wherein &amp; is &lt;RTIgt;CH2CH=CH-C3-C6 cycloalkyl or heterocycloalkyl, wherein the carbon-carbon double bond has a Z configuration. 132252 -37. 200914452 In another embodiment, the invention provides a compound of formula i, wherein R_5 is CH=CH-CH2-C:3-Q cyclodyl or heterocycloalkyl, wherein carbon-carbon double The key has an E configuration. In another embodiment, the invention provides a compound of formula I, the center of which is CH=CH-CH2-(:3-C6 cycloalkyl or heterocycloalkyl, wherein the carbon-carbon double bond has a Z configuration In another more specific embodiment, the present invention provides a hydrazine compound of the formula wherein R5 is (chr0)w C:3 -C; 6-ringed or heterocycloalkyl, wherein cycloalkyl or heterocycloalkane The base is monosubstituted. In another specific embodiment, the invention provides a compound of formula I, wherein 5 is CH=CH-CH2-C:3-C:6 cycloalkyl or heterocycloalkyl or CH =CH_C3 %cycloalkyl or heterocycloalkyl, wherein a cycloalkyl or heterocycloalkyl group is monosubstituted. In another embodiment, the invention provides a compound of formula I wherein is converted to decane-decane In another embodiment, the invention provides a compound of formula J wherein q is zero ' and Rs is CHrC4.alkyl or CH2-C5-alkyl. In another embodiment, the invention Provided is a compound of formula J wherein R5 is C2-C6 alkynyl. In another embodiment, the invention provides a compound of formula J, wherein R5 is C2-C6 alkenyl. In an embodiment, the invention provides a compound of formula IA1, IA2, IA3, IA4 or IA5, wherein X is hydrazine, r2, R, and H, and q = zero. In another specific embodiment, the invention is Provided are compounds of formula IB1, IB2, m3, 132252-38-200914452 IB4 or IB5, wherein χ is 〇, &amp;, R, and r^h, and ^0. In a more particular embodiment, the invention is Provided are compounds of hydrazine, IA2, IA3 ΙΑ4 or 1A5 wherein X is hydrazine, r2 and R are H, &amp; and the heart is methyl or methoxy, and q = zero. In another embodiment The invention provides a compound of formula IB1, iB3, IB4 or IB5 wherein χ is 〇, R^R, is H, and the heart is thiol or methoxy, and q = zero.

於項更特殊亞屬具體實施例中，本發明係提供或意欲 涵蓋任何式roi-ros化合物，其中χ為〇; q=1; 丫為〇;且士 為CVQ烷基、CH2_C3_Q環烷基、CH=CH_C3 _C6環烷基或 CH=CH-CH2-C3-(Vf、烷基。 本發明係提供或意欲涵 於又更特殊亞屬具體實施例中 盎任何式IB1-IB5化合物，其令又為〇; q叫；丫為〇;且心 為被曱氧基、曱硫基或鹵素取代之q _C6烷基。 於一項更特殊具體實施例中，本發明係提供式iAl、M2、 IA3、IA4或IA5化合物，其中χ^〇，心與汉，為h，心盘r 為甲基或甲氧基，心為。％烷基，且q =零。 4 於另一項具體實施例中，本發明係提供SIB1、IB2、IB3、 IB4或1B5化合物，其中X為〇，心與尺，為H， 或甲氧基，R5為C5 -c6烷基，且q =零。 發明詳述 R3與R4為甲基 於本文中使用之雜環烧基一詞表示飽和碳環族部份基 團，其中一或多個環碳原子係被選自Ο、N及S之原子： 換。於本文中使用之雜提，膝甘 _ ± oo &lt;雜％烯基一詞表示單-或多不飽和碳環 132252 -39- 200914452 族部份基團，其中一或多個環碳原子係被選自Ο、N及S之 原子置換。於本文中使用之雜芳基一詞表示單-或雙環狀芳 族環系統，具有一或多個等於Ο、N及/或S之環原子。 預言實例 下文實例係意欲說明-而非限制-被本發明所涵蓋化合物 之範圍。In a more specific sub-specific embodiment, the present invention provides or intends to encompass any of the formula roi-ros compounds wherein hydrazine is hydrazine; q = 1; hydrazine is hydrazine; and is CVQ alkyl, CH2_C3_Q cycloalkyl, CH=CH_C3 _C6 cycloalkyl or CH=CH-CH2-C3-(Vf, alkyl. The present invention provides or intends to encompass any of the compounds of the formula IB1-IB5 in a more specific sub-specific embodiment, which Is 〇; q is called 丫; 心 is 〇; and the heart is q _C6 alkyl substituted by oxime, thiol or halogen. In a more specific embodiment, the invention provides formulas iAl, M2, IA3 , IA4 or IA5 compound, wherein χ^〇, heart and han, h, heart plate r is methyl or methoxy, heart is .% alkyl, and q = zero. 4 In another embodiment The present invention provides a compound of SIB1, IB2, IB3, IB4 or 1B5 wherein X is hydrazine, heart and scale, H, or methoxy, R5 is C5-c6 alkyl, and q = zero. The term "heterocyclic alkyl" as used herein in the context of R4 is a saturated carbocyclic moiety, wherein one or more of the ring carbon atoms are selected from the group consisting of ruthenium, N and S: in As used herein, the term "hetero-allo" refers to a mono- or polyunsaturated carbocyclic ring 132252-39-200914452 group moiety in which one or more ring carbon atoms are selected from Atomic substitution of Ο, N and S. The term heteroaryl as used herein denotes a mono- or bicyclic aromatic ring system having one or more ring atoms equal to Ο, N and/or S. The following examples are intended to illustrate, rather than limit, the scope of the compounds encompassed by the present invention.

132252 -40- 200914452132252 -40- 200914452

132252 -41 - 200914452132252 -41 - 200914452

CF, OHCF, OH

〇〇

132252 -42- 200914452132252 -42- 200914452

132252 -43 - 200914452132252 -43 - 200914452

132252 •44- 200914452132252 •44- 200914452

〇 132252 -45 - V200914452〇 132252 -45 - V200914452

132252 -46- 200914452132252 -46- 200914452

132252 -47- 200914452132252 -47- 200914452

ClCl

132252 -48- 200914452132252 -48- 200914452

化合物之製備Preparation of compounds

作為潛在KCNQ通道開啟劑之化合物之製備 段落I.式VIII化合物之製備係概述於圖式1中。 圖式1 :Preparation of Compounds as Potential KCNQ Channel Openers Paragraph I. The preparation of compounds of Formula VIII is outlined in Scheme 1. Figure 1:

段落II.式XI化合物之製備係概述於圖式2中。 132252 49- 200914452 圖式2 :Paragraph II. The preparation of the compound of formula XI is outlined in Scheme 2. 132252 49- 200914452 Figure 2:

段落III.式XIV化合物之製備係概述於圖式3中。Paragraph III. The preparation of the compound of formula XIV is outlined in Scheme 3.

圖式3 :Figure 3:

ζΛ^ΝΗ2 (RsC0)20 x&quot; CH2CI2.鹼 IVζΛ^ΝΗ2 (RsC0)20 x&quot; CH2CI2. Base IV

段落IV.式XV化合物之製備係概述於圖式4中。Paragraph IV. The preparation of the compound of formula XV is outlined in Scheme 4.

段落V.式XVI化合物之製備係概述於圖式5中。 132252 50- 200914452Paragraph V. The preparation of compounds of formula XVI is outlined in Scheme 5. 132252 50- 200914452

圖式5 :Figure 5:

段落VI.式XX化合物之製備係概述於圖式6中。 圖式6 :Paragraph VI. The preparation of the compound of formula XX is outlined in Scheme 6. Figure 6:

【實施方式】[Embodiment]

實例Instance

實例1 : N-(6-(3,4-二氫異哇啉-2(1H)-基）-2,4-二甲基吡啶-3-基）-3,3-二甲基丁醯胺：Example 1: N-(6-(3,4-Dihydroisowolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutane amine:

步驟1. 2,4-二甲基菸鹼酸，la之合成Step 1. Synthesis of 2,4-dimethylnicotinic acid, la

co2h la 132252 -51 - 200914452 將2,4-二曱基於驗酸乙酯（3.58克，20毫莫耳）與NaOH水溶 液（10M，20毫升）在乙醇（20毫升）中之混合物於室溫下攪拌 24小時。使混合物冷卻至〇°c，並添加甲醇（2⑻毫升），接著 為HC1水溶液（10M)，以調整pH至7。濾出所形成之沉澱物 (NaCl)。 使過渡物濃縮至留下大約20毫升，且再一次添加曱醇 (100笔升）’以使殘留氯化鈉沉澱。重複沉殺作用（NaCl)，直 到自反應混合物之甲醇性溶液移除所有Naci為止。使混合 物濃縮至乾涸’產生la (3.01克，19,9毫莫耳，99%)。Co2h la 132252 -51 - 200914452 2,4-diindole based on a mixture of acid-purifying ethyl ester (3.58 g, 20 mmol) and aqueous NaOH (10M, 20 ml) in ethanol (20 ml) at room temperature Stir for 24 hours. The mixture was cooled to 〇 ° C, and methanol (2 (8) mL) was added, followed by aqueous HCl (10M) to adjust pH to 7. The precipitate formed (NaCl) was filtered off. The transition was concentrated to leave about 20 mL and decyl alcohol (100 liters) was added again to precipitate residual sodium chloride. The sterilizing effect (NaCl) was repeated until all Naci was removed from the methanolic solution of the reaction mixture. Concentration of the mixture to dryness afforded la (3.01 g, 19,9 mmol, 99%).

lb 步驟2. 2,4-二曱基-3-胺基!I比α定，ib之合成 將la (0.98克，6.5毫莫耳）與二氯化亞硫醯（5毫升）之混合 物加熱至60。〇，歷經丨小時。使混合物濃縮至乾涸。然後， 使混合物溶於丙酮（10毫升）中，接著添加NaN3(〇65克，1〇 笔莫耳）與水（5毫升）。將溶液加熱至7〇它，歷經丨小時。自 反應混合物蒸發丙酮，將其以鹽水洗滌，並以醋酸乙酯萃 取。使有機層以MgS〇4脫水乾燥，濃縮，及層析，產生讣（〇·585 克，4_79毫莫耳，74%)。 步驟3. 6-溴基_2,4_二甲基各胺基吡啶，u之合成 132252 -52- 200914452Lb Step 2. 2,4-Dimercapto-3-amine; I is more specific than α, and the synthesis of ib heats a mixture of la (0.98 g, 6.5 mmol) and sulfinium dichloride (5 ml). To 60. Hey, after a few hours. The mixture was concentrated to dryness. Then, the mixture was dissolved in acetone (10 ml), followed by NaN3 (? 65 g, 1 liter) and water (5 ml). The solution was heated to 7 Torr for a few hours. Acetone was evaporated from the reaction mixture, which was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO.sub.4, concentrated, and chromatographed to afford EtOAc ( 585 g, s. Step 3. 6-Bromo-2,4-dimethylisoamidopyridine, synthesis of u 132252 -52- 200914452

於叱下’將漠在二氯甲垸中之溶液（〇96克在5毫升中） 添加至轉585,4.79毫莫耳）在二氯曱烧（25亳升）中之溶液 内’歷經5分鐘。使混合物溫埶至 、 皿热主至酿，並攪拌2小時。將In the underarms' solution of the indifolid in the solution (in 96 ml in 5 ml) was added to the solution of 585, 4.79 mmoles in dichlorohydrazine (25 liters). minute. The mixture was allowed to warm to a hot dish and stirred for 2 hours. will

混合物以鹽水洗滌，以醋酸乙酯萃 日平取及層析，產生3c (0.364 克，1.81毫莫耳，38%)。 步驟4. N-(6-溴基-2,4-二甲基吡啶3其、 τ丞比疋-3-基）-3,3_二甲基丁醯胺The mixture was washed with brine, extracted with EtOAc EtOAc EtOAc (EtOAc) Step 4. N-(6-bromo-2,4-dimethylpyridine 3, τ丞 疋-3-yl)-3,3-dimethylbutyramine

Id之合成 ’Synthesis of Id ’

於lc (0.364克，ui毫莫耳）與吡啶价158毫升，2毫莫耳） 在一氯甲烷(5笔升)中之混合物内，添加第三-丁基氯化乙醯 (0.242克’ 1·8笔莫耳）。將混合物於室溫下攪掉2小時。將混 口物以皿水洗滌’並以醋酸乙酯萃取。使有機層以Μ幼ο# 脫水乾燥，濃縮’及層析，產生ld(〇361克，164毫莫耳， 91%) 〇 乂 驟 5· N_(6-(3,4-二氫異喳啉-2(1H)-基）-2,4-二甲基吡啶-3_ 基）-3,3-二甲基丁醯胺之合成 132252 -53 - 200914452In a mixture of lc (0.364 g, ui millimoles) and pyridine (158 ml, 2 mmol) in a mixture of methyl chloride (5 liters), add a third-butyl chloroacetate (0.242 g' 1. 8 pens). The mixture was stirred at room temperature for 2 hours. The mixture was washed with water and washed with ethyl acetate. The organic layer was dehydrated and dried, concentrated and chromatographed to give ld (〇361 g, 164 mmol, 91%) 55·N_(6-(3,4-dihydroisoindole) Synthesis of porphyrin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutyramine 132252 -53 - 200914452

於管件中，使Id (0.299克，1.0毫莫耳）、1,2,3,4-四氳異4 4 (0.20克，1.5毫莫耳）在甲苯（1〇毫升）中之混合物藉由氮流動 15分鐘而脫氣。於此混合物中，添加參（二氯苯亞曱基丙酮） 鈀（0) (0·〇46克，〇.〇5毫莫耳）、2_二環己基膦基-2'-(n，N-二甲胺 基）聯苯(0.06克，0.15毫莫耳）及第三-丁醇鉀（0.168克，1.5毫 莫耳）。將管件在微波照射（Biotage Initiator®)下，於l〇〇°c下加 熱2小時。使反應混合物冷卻至室溫，以水洗滌，並以醋酸 乙酯萃取。將有機層以鹽水洗滌，以MgS04脫水乾燥，濃縮， 及層析，產生標題產物（0.278克，0.79毫莫耳，79%)。1H NMR (CDC13, 400 MHz) 5 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 3.84 (t, J = 6.2 Hz, 2H), 4.66 (s, 2H), 6.39 (s, 1H), 6.49 (bs, 1H), 7.15-7.19 (m, 4H). 實例2:&gt;1-(6-(6-氟基-3,4-二氫異〇奎1»林-2(出)-基）-2,4-二甲基17比 啶-3-基）-3,3-二甲基丁醯胺In the tube, a mixture of Id (0.299 g, 1.0 mmol), 1, 2, 3, 4-tetraiso 4 4 (0.20 g, 1.5 mmol) in toluene (1 mL) was used. The nitrogen flowed for 15 minutes and was degassed. In this mixture, ginseng(dichlorophenylhydrazinylacetone) palladium (0) (0·〇46 g, 〇.〇5 mmol), 2_dicyclohexylphosphino-2'-(n, N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.168 g, 1.5 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 2 hours at 10 °C. The reaction mixture was cooled to room temperature, washed with water and ethyl acetate. The organic layer was washed with EtOAc (EtOAc m. 1H NMR (CDC13, 400 MHz) 5 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 3.84 (t, J = 6.2 Hz, 2H), 4.66 (s, 2H), 6.39 (s, 1H), 6.49 (bs, 1H), 7.15-7.19 (m, 4H). Example 2: &gt;1-(6 -(6-Fluoro-3,4-dihydroisoindole 1»林-2(出)-yl)-2,4-dimethyl 17-pyridin-3-yl)-3,3-dimethyl Butylamine

於管件中，使Id (0_65克’ 2.15毫莫耳）、6_氟基^3,4,氫 異喳啉（0_348克’ 2.6毫莫耳）在甲苯（15毫升）中之混合物藉 由氮流動15分鐘而脫氣。於此混合物中，添加參（二氯苯亞 甲基丙酮）鈀（〇) (0.052克，〇·〇55毫莫耳）、2_二環己基鱗基 -2'-(N，N-二甲胺基）聯苯（0.08克，0.2毫莫耳）及第三·丁醇钟 132252 -54- 200914452 (0.437克，3.9毫莫耳·）。將管件在微波照射（Biotage Initiator®) 下，於100°C下加熱6小時。使反應混合物冷卻至室溫，以 水洗滌，並以醋酸乙酯萃取。將有機層以鹽水洗滌，以MgS04 脫水乾燥，濃縮，及層析，產生標題化合物（0.584克，1.58 毫莫耳，73%)。W NMR (CDC13, 400MHz) 5 1.14 (s，9H)，2.19 (s， 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J = 6.2 Hz, 2H), 3.82 (t, J = 6.2 Hz, 2H), 4.62 (s, 2H), 6.38 (s, 1H), 6.50 (bs, 1H), 6.85-6.92 (m, 2H), 7.09-7.16 (m, 1H). 實例3 : N-(2,4-二甲基-6-(6-(三氟甲基）_3,4·二氫異喳啉_2(ih)_ 基）吡啶-3-基）-3,3-二甲基丁醯胺In the tube, a mixture of Id (0_65 g ' 2.15 mmol), 6-fluoro group ^ 3, 4, hydroisoindoline (0-348 g '2.6 mmol) in toluene (15 ml) was used for nitrogen. It was degassed by flowing for 15 minutes. To this mixture, ginseng (dichlorobenzylideneacetone) palladium (〇) (0.052 g, 〇·〇 55 mmol), 2_dicyclohexyl squara-2'-(N,N-di) Methylamino)biphenyl (0.08 g, 0.2 mmol) and a third butanol clock 132252-54-200914452 (0.437 g, 3.9 mmol). The tube was heated at 100 ° C for 6 hours under microwave irradiation (Biotage Initiator®). The reaction mixture was cooled to room temperature, washed with water and ethyl acetate. The organic layer was washed with EtOAc EtOAc m. W NMR (CDC13, 400MHz) 5 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J = 6.2 Hz, 2H), 3.82 ( t, J = 6.2 Hz, 2H), 4.62 (s, 2H), 6.38 (s, 1H), 6.50 (bs, 1H), 6.85-6.92 (m, 2H), 7.09-7.16 (m, 1H). 3 : N-(2,4-Dimethyl-6-(6-(trifluoromethyl)_3,4·dihydroisoindoline_2(ih)-yl)pyridin-3-yl)-3, 3-dimethylbutyramine

於管件中，使Id (0.374克’ 1.25毫莫耳）、6_三氟曱基_1,2,3,4-四氫異喹啉（0.301克，1.5毫莫耳）在甲苯（15毫升）中之混合 物藉由氮流動15分鐘而脫氣。於此混合物中，添加參（二氣 笨亞曱基丙酮）|巴（0) (0.037克，0.04毫莫耳）、2-二環己基膦基 -2'-(N，N-二甲胺基）聯苯（0_06克，〇15毫莫耳）及第三_丁醇鉀 (0.336克，3.0毫莫耳）。將管件在微波照射（Bi〇tage initiat〇r®) 下，於100 C下加熱6小時。使反應混合物冷卻至室溫，以 水洗滌，並以醋酸乙酯萃取。將有機層以鹽水洗滌，以MgS〇4 脫水乾燥，濃縮，及層析，產生標題化合物（〇 326克，〇 78 笔莫耳 ’ 63%)。4 NMR (CDC13,400MHz) δ 1.14 (s, 9H)，2.19 (s, 3Η), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J = 6.2 Hz, 2H), 3.82 (t, J = 6.2 Hz, 132252 -55- 200914452 2H), 4.62 (s, 2H), 6.39 (s, 1H), 6.55 (bs, 1H), 6.98 (d, J = 7.2 Hz, 2H) 7 24 (s, 1H). ’ ’ 實例4 : N-(2-(3,4-二氫異喳啉_2(1]9)_基M,6_二甲氣基嘧啶j 基）-3,3-二甲基丁酷胺In the tube, Id (0.374 g '1.25 mmol), 6-trifluorodecyl-1,2,3,4-tetrahydroisoquinoline (0.301 g, 1.5 mmol) in toluene (15 ml) The mixture was degassed by flowing nitrogen for 15 minutes. In this mixture, add ginseng (diqi sulfoximine)|bar (0) (0.037 g, 0.04 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine Biphenyl) (0_06 g, 〇15 mmol) and third potassium butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Bi〇tage initiat〇r®) at 100 C for 6 hours. The reaction mixture was cooled to room temperature, washed with water and ethyl acetate. The organic layer was washed with EtOAc (EtOAc m.). 4 NMR (CDC13, 400MHz) δ 1.14 (s, 9H), 2.19 (s, 3Η), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J = 6.2 Hz, 2H), 3.82 ( t, J = 6.2 Hz, 132252 -55- 200914452 2H), 4.62 (s, 2H), 6.39 (s, 1H), 6.55 (bs, 1H), 6.98 (d, J = 7.2 Hz, 2H) 7 24 ( s, 1H). ' ' Example 4 : N-(2-(3,4-Dihydroisoindoline_2(1)9)-yl M,6-dimethylpyrimidinylj)-3,3 - dimethylbutanamine

步驟1. 2-氯基-4,6-二甲氧基·5_硝基嘧啶，4a之合成Step 1. Synthesis of 2-chloro-4,6-dimethoxy-5-nitropyrimidine, 4a

4a 於oc下’將二氟甲烧績軒（4·25克，15毫莫耳）添加至四 甲基硝酸銨（2_04克，15毫莫耳）在二氯甲烷（4〇毫升）中之殮 浮液内，歷經15分鐘。使混合物溫熱至室溫，並攪拌2小時^ 然後，將2-氯基-4,6-二甲氧基嘧啶之溶液（1.75克，在1〇毫升 中，10宅莫耳）添加至混合物中，歷經3〇分鐘。將混合物攪 拌2天。將反應混合物倒入冰浴中，以NaHC〇3水溶液洗滌， 並以二氯甲烷萃取。以鹽水洗滌有機層，濃縮至乾涸，產 生 4a (2.13 克，9_73 毫莫耳，97%)。 步驟2. 2-(4,6-二曱氧基_5_硝基嘧啶_2_基）-1，2,3,4-四氫異嗜 啉，4b之合成 132252 -56- 200914452 p—4a under oc' Add fluorocarbonate (4·25 g, 15 mmol) to tetramethylammonium nitrate (2_04 g, 15 mmol) in dichloromethane (4 mL) In the floating liquid, it took 15 minutes. The mixture was allowed to warm to room temperature and stirred for 2 hours. Then, a solution of 2-chloro-4,6-dimethoxypyrimidine (1.75 g in 1 mL, 10 mmol) was added to the mixture. In, it took 3 minutes. The mixture was stirred for 2 days. The reaction mixture was poured into an ice-bath, washed with a NaH. The organic layer was washed with brine and concentrated to dryness to yield 4a (2,3 g, Step 2. Synthesis of 2-(4,6-dimethoxyoxy-5-nitropyrimidin-2-yl)-1,2,3,4-tetrahydroisomorpholine, 4b 132252 -56- 200914452 p-

於0 C下’將1，8-二氮雙環并[5.4.0]十一 -7-烯（0.304克，2毫 莫耳）添加至4a (0.438克，2毫莫耳）與1,2,3,4-四氫異喹啉（0.293 克’ 2.2毫莫耳）在DMF (3毫升）中之混合物内，歷經5分鐘。 將混合物於室溫下再攪拌5分鐘。將混合物以鹽水洗滌，以 醋酸乙酯萃取’及層析，產生4b (0_592克，1.87毫莫耳，94%)。 步驟3. 2-(3,4-二氫異喹啉_2(1H)-基）-4,6-二曱氧基嘧啶-5-胺， 4c之合成Add 1,8-diazabicyclo[5.4.0]undec-7-ene (0.304 g, 2 mmol) to 4a (0.438 g, 2 mmol) and 1,2 at 0 C 3,4-Tetrahydroisoquinoline (0.293 g '2.2 mmol) in a mixture of DMF (3 mL) over 5 min. The mixture was stirred for a further 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and then purified to afford 4b (0-592 g, 1.87 m. Step 3. Synthesis of 2-(3,4-dihydroisoquinoline-2(1H)-yl)-4,6-dimethoxypyrimidine-5-amine, 4c

使Raney®-錄在4b之曱醇性溶液（〇_57克，在50毫升中，h8 毫莫耳）之懸浮液於50 psi之氫大氣下振盪12小時。過渡混 合物’並使濾液濃縮，且使用於下一步驟，無需進一步純 化（0_51 克，1.78 毫莫耳，99%)。 步驟4· N-(2-(3,4-二氫異喹啉-2(1H)-基）_4,6-二甲氧基鳴咬_5 基）-3,3-二甲基丁醯胺，4d之合成A suspension of Raney®-labeled 4b sterol solution (〇_57 g in 50 ml, h8 mmol) was shaken under a hydrogen atmosphere of 50 psi for 12 hours. The transition mixture was allowed to concentrate and was used in the next step without further purification (0-51 g, 1.78 mmol, 99%). Step 4· N-(2-(3,4-Dihydroisoquinolin-2(1H)-yl)_4,6-dimethoxy-biting _5-yl)-3,3-dimethylbutane Amine, synthesis of 4d

4d 132252 -57- 200914452 於4C (0.219克，0.76毫莫耳）與吡啶（0.06克，0.76毫莫耳） 在二氯甲烷（5毫升）中之混合物内，添加第三-丁基氣化乙醯 (0-102克’ 〇,76毫莫耳）。將混合物於室溫下攪拌1小時。將 此合物以鹽水洗務，並以醋酸乙醋萃取。使有機層以MgS04 脫水乾燥’濃縮’及層析，產生標題化合物（〇·262克，〇 73 毫莫耳，96%)。iH NMR (CDC13, 400MHz) 5 1.10 (s，9Η)，2.20 (s，4d 132252 -57- 200914452 Adding a third-butyl group B to a mixture of 4C (0.219 g, 0.76 mmol) and pyridine (0.06 g, 0.76 mmol) in dichloromethane (5 mL)醯 (0-102 grams ' 〇, 76 millimoles). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; iH NMR (CDC13, 400MHz) 5 1.10 (s, 9Η), 2.20 (s,

2H), 2.90 (tj j = 5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J = 5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H). 實例5 : N-(4,6-二甲氧基-2-(6-(三氟甲基）_3,4_二氫異喳啉 •2(1H)-基）σ密啶_5_基）_3,3_二甲基丁醯胺2H), 2.90 (tj j = 5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J = 5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H). Example 5: N-(4,6-Dimethoxy-2-(6-(trifluoromethyl)_3,4-dihydroisoindoline•2(1H)-yl)σ Midine _5_yl)_3,3-dimethylbutyramine

步驟1.參考實例4 步驟2. 2-(4,6-二曱氧基-5-硝基嘧啶_2_基三氟曱 基）-1,2,3,4-四氫異喹啉，5b之合成Step 1. Reference Example 4 Step 2. 2-(4,6-Dimethoxy-5-nitropyrimidin-2-yltrifluoromethyl)-1,2,3,4-tetrahydroisoquinoline, Synthesis of 5b

5b 於0 C下’將1，8-二氮雙環并[5.4.0]十—_7_烯（ο·克，4.4毫 莫耳）添加至4a (0.438克’ 2毫莫耳）與6_(三氟甲基H，2,3,4_ra 氫異4啉鹽酸鹽（0.487克，2.05毫莫耳）在131^ (5毫升）中之 扣合物内，歷經5分鐘。將混合物於室溫下再攪拌5分鐘。 132252 -58- 200914452 將混合物以鹽水洗滌，以醋酸乙酯萃取， (0.76克’ 1.98毫莫耳’ 99%)。 折產生5b 異喳啉-2(1 H)- 步驟3_ 4,6-二甲氧基·2_(6_(三氟甲基）_3,4_二氣 基）鳴°定-5-胺，5c之合成5b at 0 C 'Add 1,8-diazabicyclo[5.4.0] dec-_7-ene (ο·g, 4.4 mmol) to 4a (0.438 g '2 mmol) and 6_( Trifluoromethyl H, 2,3,4_ra hydroiso-isolinoline hydrochloride (0.487 g, 2.05 mmol) in a mixture of 131^ (5 mL) over 5 min. The mixture was stirred for another 5 minutes. 132252 -58- 200914452 The mixture was washed with brine and extracted with ethyl acetate (0.76 g &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& Synthesis of 3_ 4,6-dimethoxy·2_(6-(trifluoromethyl)_3,4_diyl)amine-5-amine, 5c

FF

使Raney®-鏡在Sb之甲醇性溶液（〇 76克，在5〇毫升中，1 % 毫莫耳）中之懸浮液於5〇 psi之氫大氣下振心小時。過渡 混合物，並錢液濃縮，且使用於下_步驟，&amp;需進―步 純化（0.69克’ 1.96毫莫耳，99%)。 步驟4· N-(4,6-二甲氧基邻_(三氟甲基）_3,4_二氫異喹啉 -2(1H)-基）嘧啶-5-基）-3,3-二甲基丁醯胺之合成A suspension of Raney®-mirror in a methanolic solution of Sb (〇 76 g in 5 mL, 1% millimolar) was vortexed in a hydrogen atmosphere at 5 psi. The mixture was allowed to flow and the solution was concentrated and used in the next step, &amp;&lt;RTIID=0.0&gt;&gt; Step 4· N-(4,6-Dimethoxy-o-(trifluoromethyl)_3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-yl)-3,3- Synthesis of dimethylbutyric acid

於5e (0_69克，1_96毫莫耳）與吡啶（〇 156克，2 〇毫莫耳）在 二氯甲烷（20毫升）中之混合物内，添加第三_丁基氣化乙醯 (0.269克，2.0毫莫耳）。將混合物於室溫下攪拌}小時。將混 合物以鹽水洗猶；，並以醋酸乙酯萃取。使有機層以MgS〇4 脫水乾燥’濃縮，及層析’產生標題化合物（〇 657克，；1.45 宅莫耳，72%)。4 NMR (CDC13, 400MHz) (5 1.10 (s，9H)，2.20 (s, 2H), 2.95 (t, J = 5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J = 5.8 Hz, 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J - 7.8 Hz, 1H). 實例6:：^-(2-(3,4-二氫異喳啉-2(111)-基）-4,6-二甲基嘧啶-5- 132252 -59· 200914452 基）-3,3-Add a third _butyl acetonitrile (0.269 g) in a mixture of 5e (0-69 g, 1 - 96 mmol) and pyridine ( 156 g, 2 mmol) in dichloromethane (20 mL) , 2.0 millimoles). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine; and extracted with ethyl acetate. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; 4 NMR (CDC13, 400MHz) (5 1.10 (s, 9H), 2.20 (s, 2H), 2.95 (t, J = 5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J = 5.8 Hz , 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J - 7.8 Hz, 1H). 6::^-(2-(3,4-Dihydroisoindoline-2(111)-yl)-4,6-dimethylpyrimidine-5-132252 -59· 200914452))-3,3-

步驟1. 2-羥基-4,6-二曱基嘧啶-5-Step 1. 2-Hydroxy-4,6-dimercaptopyrimidine-5-

羧酸乙酯， 如之合成Ethyl carboxylate, as synthesized

6a6a

將二乙醯醋酸乙酯（17.22克，1〇〇毫莫耳）、尿素（9·61克， 160毫莫耳）及HC1 (10Μ，4毫升）在乙醇（4〇〇毫升）中之混合 物加熱至90。(：，歷經12小時。使混合物濃縮至留下2〇〇毫升’ 然後冷卻至-2(TC，以使其沉澱。將混合物於室溫下過濾， 獲得6a ’為固體顆粒（5.32克，2.71毫莫耳，27%)。 步驟2. 2-氯基-4,6-二甲基嘧啶-5-羧酸乙酯6b之合成a mixture of diethyl acetate (17.22 g, 1 mmol), urea (9. 61 g, 160 mmol) and HCl (10 Torr, 4 ml) in ethanol (4 mL) Heat to 90. (:, after 12 hours. Concentrate the mixture to leave 2 mL) and then cool to -2 (TC) to precipitate. The mixture was filtered at room temperature to obtain 6a' as solid particles (5.32 g, 2.71) Miller, 27%). Step 2. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate 6b

Cl\ , 〜口 &quot;ΛιCl\ , 〜口 &quot;Λι

6b 將氯化碟醯（2.8毫升’ 30毫莫耳）添加至6a (1.47克，7.5毫 莫耳）、苄基三乙基氯化銨（1.71克，7.5毫莫耳）及Ν,Ν-二曱 本月女（1.82克，15毫莫耳）在乙赌（3〇毫升）中之混合物内。使 忍合物回流5小時。將混合物倒入冰水中，並以NaHC03中 和。以醋酸乙酯萃取溶液。將有機層以鹽水洗滌，以MgS〇4 脫水乾燥，濃縮，及層析，獲得6b (1.02克，4.75毫莫耳，63%)。 步驟3· 2-(3,4_二氫異p奎淋_2(1H)-基）-4,6-二甲基。密咬-5-缓酸 132252 -60- 200914452 乙酯，6c之合成6b Add chlorinated dish (2.8 ml '30 mmol) to 6a (1.47 g, 7.5 mmol), benzyl triethylammonium chloride (1.71 g, 7.5 mmol) and Ν, Ν- Second, this month's female (1.82 grams, 15 millimoles) in a mixture of B gambling (3 liters). The tolerant was refluxed for 5 hours. The mixture was poured into ice water and neutralized with NaHC03. The solution was extracted with ethyl acetate. The organic layer was washed with brine, dried with EtOAc EtOAc EtOAc EtOAc. Step 3· 2-(3,4-dihydroiso-p-quinone-2(1H)-yl)-4,6-dimethyl. Mickey-5-sodium acid 132252 -60- 200914452 Ethyl ester, synthesis of 6c

於 〇°C 下’將 1,8-二氮雙環并[5.4.0]十一 -7-烯（1·086 克，7.15 毫莫耳）添加至6b (1.02克’ 4.75毫莫耳）與l，2,3,4-四氫異喳啉 (0.95克’ 7.13¾莫耳）在DMSO (5毫升）中之混合物内，歷經5 分鐘。將混合物於室溫下再攪拌5分鐘。將混合物以鹽水洗 條，以醋酸乙酯萃取，及層析，產生6c (143克，4·5毫莫耳’ 95%)。 步驟4· 2-(3,4·二氫異喳啉_2(1Η)-基）-4,6-二曱基嘧啶-5-羧酸， 6d之合成Add 1,8-diazabicyclo[5.4.0]undec-7-ene (1·086 g, 7.15 mmol) to 6b (1.02 g ' 4.75 mmol) at 〇 ° ° C l, 2,3,4-Tetrahydroisoindoline (0.95 g ' 7.133⁄4 mol) in a mixture of DMSO (5 mL) over 5 min. The mixture was stirred for a further 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to afford 6c (143 g, 4. 5 mM &apos; 95%). Step 4· 2-(3,4·Dihydroisoindoline_2(1Η)-yl)-4,6-dimercaptopyrimidine-5-carboxylic acid, synthesis of 6d

使6c (1.43克’ 4.5毫莫耳）與Na〇H水溶液（1〇M，20毫升） 在乙醇（20毫升）中之混合物回流6小時。於混合物中添加 100毫升水，然後，以二氣甲烷（100毫升）洗滌混合物。以鹽 酸使水相中和至PH=6。在PH=6下使產物沉澱。於過濾後， 獲付6d，為自色粉末（1.10克，3.88毫莫耳，86%)。 步驟5· 2-(3,4-二氫異喳啉_2(1H)_基）_4,6·二曱基嘧啶_5_胺，6e 之合成 132252 -61 - 200914452A mixture of 6c (1.43 g, &lt;RTI ID=0.0&gt;&gt; 100 ml of water was added to the mixture, and then the mixture was washed with dioxane (100 ml). The aqueous phase was neutralized with hydrochloric acid to pH = 6. The product was precipitated at pH = 6. After filtration, 6 d was obtained as a self-color powder (1.10 g, 3.88 mmol, 86%). Step 5· 2-(3,4-Dihydroisoindoline_2(1H)-yl)_4,6·dimercaptopyrimidine-5-amine, synthesis of 6e 132252 -61 - 200914452

於冷（-20°C )二氯化亞硫醯（5毫升）中，添加9d (〇·8克，2 82 歷經1小時。蒸發過量二 宅莫耳）。將混合物加熱至7〇。(2， 氯化亞硫醯。使殘留物溶於THF 毫升）與丙酮（3毫升）中， 然後’將疊氮化三甲基矽烷（〇·55毫升，4 25毫莫耳）添加至 混合物中。將混合物加熱至7(rc，歷經2小時。以鹽水洗滌 反應媒質，以醋酸乙酯萃取。使有機層以MgS〇4脫水乾燥， 濃縮’及層析，產生6e (0.028克，0.11毫莫耳，4%)。 步驟6. N-(2-(3,4-二氫異p奎琳·2(1Η)-基）-4,6-二甲基。密咬-5-基）-Ν-(3,3-二甲基丁醯基）_3,3_二甲基丁醯胺，6f之合成In a cold (-20 ° C) sulphur dichloride sulphate (5 ml), 9d (〇·8 g, 2 82 over 1 hour. Evaporation of excess methane) was added. The mixture was heated to 7 Torr. (2, sulfinium chloride. Dissolve the residue in THF ml) with acetone (3 ml), then add trimethyl decyl azide (〇·55 ml, 4 25 mmol) to the mixture. in. The mixture was heated to 7 (rc) over 2 hours. The reaction medium was washed with brine and extracted with ethyl acetate. The organic layer was dried with &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&& , 4%). Step 6. N-(2-(3,4-Dihydroiso-p-quinein 2(1Η)-yl)-4,6-dimethyl. Bite-5-yl)-Ν -(3,3-Dimethylbutanyl)_3,3-dimethylbutyramine, synthesis of 6f

於6e (〇·〇28克，0.11毫莫耳）與吡啶（〇.〇3克，0.4毫莫耳）在 二氣甲烷（2毫升）中之混合物内’添加第三-丁基氯化乙醯 (0.053克’ 0.4毫莫耳）。將混合物於室溫下攪拌5小時。將混 合物以鹽水洗滌’並以醋酸乙酯萃取。使有機層以MgS〇4 脫水乾燥’濃縮，及層析’產生6f (0.031克，0.07毫莫耳， 63%)。 132252 • 62· 200914452 步驟7. N-(2-(3,4-二氫異喳啉-2(1H)-基）-4,6-二甲基嘧啶-5-基）-3,3-二甲基丁醯胺之合成Adding a third-butyl chloride to a mixture of 6e (〇·〇28g, 0.11 mmol) and pyridine (〇.〇3 g, 0.4 mmol) in di-methane (2 mL)醯 (0.053 g '0.4 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dehydrated to dryness &lt;RTI ID=0.0&gt;&gt;&gt; 132252 • 62· 200914452 Step 7. N-(2-(3,4-Dihydroisoindoline-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-3,3- Synthesis of dimethylbutyric acid

將氫氧化銨水溶液（30%，1毫升）添加至6f (0.031克，〇.〇7 毫莫耳）在曱醇（1毫升）中之溶液内，並攪拌20小時。將混 合物以鹽水洗滌，且以醋酸乙酯萃取。使有機層以MgS04 脫水乾燥，濃縮，及層析，產生標題化合物（0.019克，0.054 毫莫耳 ’ 77%)。NMR (CDC13, 400MHz) (5 1· 11 (s, 9H), 2.23 (s, 2H), 2.30 (Sj 6H), 2.91 (t, J = 6.0 Hz, 2H), 4.04 (t, J = 6.0 Hz, 2H), 4.89 (s, 2H), 6.68 (s, 1H), 7.17 (dd, J = 7.8, 3.4 Hz, 4H). 實例7:斗(6-(6-氟基-3,4-二氫異4啉_2(1印-基）-2,4-二甲基吡 咬-3-基）-2-(2-甲氧基乙氧基）乙醯胺 步驟1· N-(6-溴基-2,4-二甲基吡啶_3_基）-2-(2-曱氧基乙氧基） 乙酿胺之合成 △Vo 〜。、 7d 於lc (0.5114克，2.54毫莫耳）與吡啶（〇·22毫升，2 78毫莫耳） 在一氣曱烷（5毫升）中之混合物内，添加2_(2_甲氧基乙氧基） 氯化乙醯（0.425克，2·78毫莫耳）。將混合物於室溫下攪拌土過 夜。將混合物以鹽水洗務，纟以醋酸乙酷萃取。使有機層 以MgS〇4脫水乾燥，濃縮，及層析，產生？d(〇·72克，2刀^ 莫耳，90%)。 · 132252 -63 - 200914452 步驟2.&gt;1-(6-(6-氟基-3,4-二氫異喳啉-2(111)-基）-2,4-二曱基吡 °定-3-基）-2-(2-甲氧基乙氧基）乙酸胺An aqueous solution of ammonium hydroxide (30%, 1 ml) was added to a solution of 6f (0.031 g, 〇. 〇7 mmol) in methanol (1 ml) and stirred for 20 hr. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried <RTI ID=0.0>(M </RTI> </RTI> <RTI ID=0.0> NMR (CDC13, 400MHz) (5 1· 11 (s, 9H), 2.23 (s, 2H), 2.30 (Sj 6H), 2.91 (t, J = 6.0 Hz, 2H), 4.04 (t, J = 6.0 Hz) , 2H), 4.89 (s, 2H), 6.68 (s, 1H), 7.17 (dd, J = 7.8, 3.4 Hz, 4H). Example 7: Bucket (6-(6-fluoro-3,4-di) Hydroisoisoline-2 (1 - yl)-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide Step 1 · N-(6 -Bromo-2,4-dimethylpyridine-3-yl)-2-(2-decyloxyethoxy) Synthesis of ethanoamine △Vo ~., 7d in lc (0.5114 g, 2.54 mmol) To the mixture of pyridine (〇·22 ml, 2 78 mmol) in a mixture of monooxane (5 ml), add 2-(2-methoxyethoxy)ethyl chloride (0.425 g, 2 · 78 mmol.) The mixture was stirred overnight at room temperature. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried with EtOAc EtOAc. (〇·72 g, 2 knives ^ Moule, 90%) · 132252 -63 - 200914452 Step 2.&gt; 1-(6-(6-Fluoro-3,4-dihydroisoindoline-2) 111)-yl)-2,4-dimercaptopyridin-3-yl)-2-(2-methoxyethoxy)acetic acid amine

於管件中，使7d (0.245克，0.77毫莫耳）、6-氟基-1,2,3,4-四 • 氫異喳啉（0.丨876克’ 1.0毫莫耳）在甲苯（5毫升）中之混合物 藉由氮流動15分鐘而脫氣。於此混合物中，添加參（二氯苯 f ' 亞甲基丙酮）鈀⑼（0.025克，0.027毫莫耳）、2-二環己基膦基 -2’-(N，N-二甲胺基）聯苯（〇.〇4克，〇.i毫莫耳）及第三_丁醇鉀 (0.336克’ 3·0毫莫耳）。將管件在微波照射（Bi〇tage Initiat〇r®) 下，於100°C下加熱6小時。使反應混合物冷卻至室溫，以 水洗滌’並以醋酸乙酯萃取。將有機層以鹽水洗滌，以MgS〇4 脫水乾燥’濃縮’及層析’產生標題化合物（0.259克，0.668 毫莫耳 ’ 87%)。NMR (CDC13, 400 MHz) (5 2.19 (s, 3H), 2.36 (s， 3H), 2.92 (t, J = 5.7 Hz, 2H), 3.40 (s, 3H), 3.62 (dd, J = 4.3, 2.2 Hz, 2H), ί / 3.80-3.84 (m, 4H), 4.19 (s, 2H), 4.64 (s, 2H), 6.40 (s, 1H), 6.85-6.91 (m, 2H), 7.14 (dd, J = 7.9, 7.9 Hz, 1H), 8.21 (bs, 1H). 實例8 : N-(2,4-二甲基-6-(6-(三氟甲基）_3,4_二氫異喹啉_2(1H)_ 基 &gt;比啶-3-基）-2-(2-甲氧基乙氧基）乙醯胺In the tube, 7d (0.245 g, 0.77 mmol), 6-fluoro-1,2,3,4-tetrahydroisophthalide (0. 丨 876 g '1.0 mmol) in toluene ( The mixture in 5 ml) was degassed by flowing nitrogen for 15 minutes. To this mixture, ginseng (dichlorobenzene f 'methylene acetonone) palladium (9) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamino group) was added. Biphenyl (〇.〇4 g, 〇.i millimolar) and third-butanol potassium (0.336 g '3.00 mmol). The tube was heated under microwave irradiation (Bi〇tage Initiat®®) at 100 ° C for 6 hours. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with EtOAc (EtOAc m.). NMR (CDC13, 400 MHz) (5 2.19 (s, 3H), 2.36 (s, 3H), 2.92 (t, J = 5.7 Hz, 2H), 3.40 (s, 3H), 3.62 (dd, J = 4.3, 2.2 Hz, 2H), ί / 3.80-3.84 (m, 4H), 4.19 (s, 2H), 4.64 (s, 2H), 6.40 (s, 1H), 6.85-6.91 (m, 2H), 7.14 (dd , J = 7.9, 7.9 Hz, 1H), 8.21 (bs, 1H). Example 8: N-(2,4-Dimethyl-6-(6-(trifluoromethyl)_3,4_dihydroiso Quinoline_2(1H)_yl>pyridin-3-yl)-2-(2-methoxyethoxy)acetamide

於管件中，使7d (0.2克，〇.6毫莫耳）、6_三氟曱基_1，2,3,4-四虱異嗜啦（0.209克，0.88毫莫耳）在曱苯（5毫升）中之混合 132252 -64 - 200914452 物藉由氮流動15分鐘而脫氣。於此混合物中，添加參（二氯 苯亞曱基丙酮）把（〇) (0.025克，0.027毫莫耳）、2-二環己基膦 基-2’-(N,N-二曱胺基）聯苯(〇.〇4克，0·1毫莫耳）及第三-丁醇鉀 (0.224克，2.0毫莫耳）。將管件在微波照射（Biotage Initiator®) 下，於100°C下加熱6小時。使反應混合物冷卻至室溫，以 水洗滌，並以醋酸乙酯萃取。將有機層以鹽水洗滌，以MgS04 脫水乾燥，濃縮，及層析’產生標題化合物（0.262克，0.6 毫莫耳，95%)。β NMR (CDC13, 400 MHz) 5 2.18 (s，3H)，2.35 (s, 3H), 2.96 (t, J - 5.5 Hz, 2H), 3.37 (s, 3H), 3.62 (dd, J = 3.8, 1.6 Hz, 2H), 3.78-3.84 (m, 4H), 4.17 (s, 2H), 4.71 (s, 2H), 6.41 (s, 1H), 7.27 (d, J = 7.7,1H), 7.40 (s, 1H), 7.41 (d, J = 8.4 Hz, 1H), 8.25 (bs, 1H). 貫例 9 : N-(2,4-二曱基-6-(7-(三氟甲基）-3,4_二氫異 + 4 _2(ih)_ 基）吡啶-3-基）-3,3-二甲基丁醯胺In the pipe fitting, make 7d (0.2g, 〇.6mmol), 6_trifluoromethyl-1,2,3,4-tetrahydropyrene (0.209g, 0.88mmol) in benzene The mixture of 132252-64 - 200914452 in (5 ml) was degassed by flowing nitrogen for 15 minutes. In this mixture, ginseng(dichlorophenylidene acetonide) was added (〇) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2'-(N,N-diamine group Biphenyl (〇.〇4 g, 0·1 mmol) and third-butanol potassium (0.224 g, 2.0 mmol). The tube was heated at 100 ° C for 6 hours under microwave irradiation (Biotage Initiator®). The reaction mixture was cooled to room temperature, washed with water and ethyl acetate. The organic layer was washed with EtOAc (EtOAc m. β NMR (CDC13, 400 MHz) 5 2.18 (s, 3H), 2.35 (s, 3H), 2.96 (t, J - 5.5 Hz, 2H), 3.37 (s, 3H), 3.62 (dd, J = 3.8, (6, Hz, 2H) , 1H), 7.41 (d, J = 8.4 Hz, 1H), 8.25 (bs, 1H). Example 9: N-(2,4-dimercapto-6-(7-(trifluoromethyl)- 3,4_Dihydroiso+ 4 _2(ih)_yl)pyridin-3-yl)-3,3-dimethylbutyramine

將雙（二苯亞甲基丙酮）|巴（4毫克，〇_〇69毫莫耳）與（2，_二環 己基鱗烷基-聯苯-2-基）-二甲胺（6.5毫克，0.014毫莫耳）添加 至無水甲苯（1 Φ升，以氬滌氣）中，並於氬氣下攪拌15分鐘。 然後添加第三-丁醇鉀（34毫克，0.3毫莫耳）、ld (5〇毫克，〇.17 毫莫耳）及3-(三氟甲基）-5,6,7,8-四氫_1,6_喑啶（28毫克，〇14毫 莫耳），且將反應混合物在8(TC下攪拌過夜。接著，使反應 混合物冷卻至室溫，濃縮，及藉Bi〇tage純化（75%醋酸乙醋： 己烷）’而得標題化合物，為固體。iHNMR(DMs〇_d6,4〇〇MHz) 132252 -65- 200914452 5 1.03 (s, 9H), 2.09 (s, 3H), 2.15 (s, 2H), 2.21 (s, 3H), 3.03 (t, J =： 4 Hz 2H), 3.92 (t, J = 4 Hz, 2H), 4.79 (s, 2H), 6.68 (s, 1H), 8.12 (s, 1H), 8.75 (s 1H), 9.02 (s, 1H). 實例 10: N-(6-(7,8-二氫吡啶并[4,3-d]嘧啶 _6(5h)_基）_2,4·二甲美 p比啶-3-基）-3,3-二甲基丁醯胺Bis(diphenylmethyleneacetone)|bar (4 mg, 〇_〇 69 mmol) and (2,-dicyclohexyl squarenyl-biphenyl-2-yl)-dimethylamine (6.5 mg) , 0.014 mmol) was added to anhydrous toluene (1 Φ liter, argon purge) and stirred under argon for 15 min. Then add potassium tert-butoxide (34 mg, 0.3 mmol), ld (5 mg, 〇.17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetra Hydrogen, 1, 6-acridine (28 mg, 〇 14 mmol), and the reaction mixture was stirred at 8 (TC) overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by EtOAc. 75% Acetate (hexane): hexane) 2.15 (s, 2H), 2.21 (s, 3H), 3.03 (t, J =: 4 Hz 2H), 3.92 (t, J = 4 Hz, 2H), 4.79 (s, 2H), 6.68 (s, 1H) ), 8.12 (s, 1H), 8.75 (s 1H), 9.02 (s, 1H). Example 10: N-(6-(7,8-dihydropyrido[4,3-d]pyrimidine_6 ( 5h) _ base) 2,4·dimethylpyr p-pyridin-3-yl)-3,3-dimethylbutyramine

將雙（二苯亞甲基丙酮）把（5毫克，〇 〇〇9毫莫耳）與（2，_二琿 己基磷烷基-聯苯-2-基）-二曱胺（9毫克，0.018毫莫耳）添加至 無水曱笨（1窀升，以氬滌氣）中，並於氬氣下攪拌15分鐘。 接著添加第三-丁醇鉀（46毫克，0.41毫莫耳）、ld (66毫克， 0.22毫莫耳）及5,6,7,8-四氫吡啶并[4,3-d]嘧啶（25毫克，〇·19毫莫 耳），且將反應混合物在8(TC下攪拌過夜。然後，使反應混 合物冷卻至室溫，濃縮，及藉Biotage純化（75。/。醋酸乙酯： 己烷），而得標題化合物，為固體。！ H NMR (CD%，4〇〇 δ 1.15 (s, 9Η), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.06 (t, J - 4 Hz, 2H), 3.92 (t, J = 4 Hz, 2H), 4.73 (s, 2H), 6.48 (s, 1H), 6.55 (s, 1H), 8.55 (s, 1H), 9.01 (s, 1H). 實例11 . N-(2,4-二甲基_6-(2-(三氟甲基）_7,8_二氫吡啶并[4,3_d] 嘧啶-6(5H)-基）吡啶_3_基）_3,3_二曱基丁醯胺Put bis(dibenzylideneacetone) with (5 mg, 〇〇〇9 mmol) and (2,-dihexylphosphinoalkyl-biphenyl-2-yl)-diguanamine (9 mg, 0.018 mmol was added to anhydrous hydrazine (1 liter, argon purge) and stirred under argon for 15 minutes. Then add potassium third-butoxide (46 mg, 0.41 mmol), ld (66 mg, 0.22 mmol) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine ( 25 mg, 〇19 mmol, and the reaction mixture was stirred at 8 (TC) overnight. Then, the reaction mixture was cooled to room temperature, concentrated, and purified by Biotage (75% / ethyl acetate: hexane The title compound is a solid. H NMR (CD%, 4〇〇δ 1.15 (s, 9Η), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.06 (t, J - 4 Hz, 2H), 3.92 (t, J = 4 Hz, 2H), 4.73 (s, 2H), 6.48 (s, 1H), 6.55 (s, 1H), 8.55 (s, 1H) , 9.01 (s, 1H). Example 11. N-(2,4-Dimethyl-6-(2-(trifluoromethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6 ( 5H)-yl)pyridine_3_yl)_3,3-dimercaptobutylamine

將雙（二苯亞曱基丙酮你（4毫克，〇.〇7毫莫耳）與（2，_二環己 132252 -66- 200914452 基碟烷基-聯苯-2-基）-二甲胺（6.5毫克，〇·〇14毫莫耳）添加至 無水甲苯（1毫升’以氬滌氣）中’並於氬氣下攪拌15分鐘。 接著添加第三-丁醇鉀（34毫克，0·31毫莫耳）、ld (5〇毫克， 0.18毫莫耳）及2_(三氟甲基&gt;5,6,7,8_四氫吡啶并[4,3_d]嘧啶（28 毫克’ 0.14毫莫耳），且將反應混合物在8〇。〇下擾拌過夜。 然後’使反應混合物冷卻至室溫’濃縮，及藉Bi〇tage純化Combine bis(diphenylarhenylene acetonide (4 mg, 〇.〇7 mmol) with (2,_dicyclohexane 132252-66- 200914452 base-alkyl-biphenyl-2-yl)-dimethyl Amine (6.5 mg, 〇·〇 14 mmol) was added to dry toluene (1 mL 'with argon purge) and stirred under argon for 15 min. · 31 mM), ld (5 〇 mg, 0.18 mmol) and 2 _ (trifluoromethyl) 5,6,7,8-tetrahydropyrido[4,3_d]pyrimidine (28 mg' 0.14 Milligram), and the reaction mixture was stirred overnight at 8 Torr. Then, the reaction mixture was cooled to room temperature to concentrate and purified by Bi〇tage.

(75 /〇醋酸乙醋.己院），而得化合物9，為固體。1 η nmr (CDC13, 400 MHz) (? 1.14 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.17 (t, J -4 Hz, 2H), 3.92 (t, J = 4 Hz, 2H), 4.83 (s, 2H), 6.51 (s, 1H), 8.70 (s, 1H). 生物學結果 本發明化學式之化合物係在下述檢測中藉由度量铷釋 出’而被評估為鉀通道調節劑。 方法：使PC-12細胞在37°C及5% C02下，於經補充1〇°/0馬 血清、5%牛胎兒血清、2 mM麩醯胺、1〇〇 u/毫升青黴素、 100 U/毫升鏈黴素之DMEM/F12培養基中生長。將其在4〇,〇〇() 個細胞/井之密度下覆蓋於聚_D_離胺酸塗覆之96_井細胞培 養物微板中，並以1〇〇毫微克/毫升NGF_7s分化2_5天。關於 此檢測’係將培養基吸出，並將細胞以〇2毫升在洗滌缓衝(75 / 〇 acetic acid ethyl vinegar. hexane), and the compound 9, was a solid. 1 η nmr (CDC13, 400 MHz) (? 1.14 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.17 (t, J -4 Hz, 2H) , 3.92 (t, J = 4 Hz, 2H), 4.83 (s, 2H), 6.51 (s, 1H), 8.70 (s, 1H). Biological results The compounds of the formula of the invention are measured by the following assays铷 Released and evaluated as a potassium channel modulator. Method: PC-12 cells were supplemented with 1〇°/0 horse serum, 5% fetal serum, 2 mM bran at 37 ° C and 5% CO 2 Glucosamine, 1〇〇u/ml penicillin, 100 U/ml streptomycin in DMEM/F12 medium. Cover it at 4 〇, 〇〇() cells/well density at poly_D_ Amino acid-coated 96-well cell culture microplates were differentiated for 2-5 days at 1 ng/g NGF_7s. For this assay, the medium was aspirated and the cells were buffered with 2 ml in wash buffer.

劑（25 mM Hepes，pH 7.4, 150 mM NaCl，1 mM MgCl2，0_8 mMAgent (25 mM Hepes, pH 7.4, 150 mM NaCl, 1 mM MgCl2, 0_8 mM

NaHjO4, 2 mM CaCl2)中洗滌一次。然後，將細胞裝填〇·2毫 升Rb+裝填緩衝劑（洗滌緩衝劑加上5 4 mM RbCl2 , 5 mM葡萄 糖）’並在37°C下培養2小時。將所附著之細胞以緩衝劑（與 裝填緩衝劑相同，但含有5 4 mM KQ代替RbC1)快速地洗 務三次’以移除胞外Rb+。緊接於洗滌之後，將具有或未具 132252 -67- 200914452 有化合物之0.2毫升去極化作用緩衝劑（洗滌緩衝劑加上μ mM KC1)添加至細胞中’以使钟離子通道之射流活化^於室 溫下培養10分鐘之後，小心地移除上層清液，並收集。藉 由添加0.2毫升溶胞緩衝劑（去極化作用緩衝劑加上〇以Wash once in NaHjO4, 2 mM CaCl2). Then, the cells were filled with 2 ml of Rb+ loading buffer (wash buffer plus 5 4 mM RbCl2, 5 mM glucose) and cultured at 37 ° C for 2 hours. The attached cells were washed three times with buffer (same as loading buffer but containing 5 4 mM KQ instead of RbC1) to remove extracellular Rb+. Immediately after washing, 0.2 ml of depolarization buffer (wash buffer plus μ mM KC1) with or without 132252 -67- 200914452 compound was added to the cells to activate the jet of the ion channel After incubation at room temperature for 10 minutes, the supernatant was carefully removed and collected. By adding 0.2 ml of lysis buffer (depolarization buffer plus hydrazine

Triton X-100)使細胞溶解，且亦收集細胞溶胞產物。若所收 集之試樣未立即藉由原子吸收光譜學（參閱下文）分析關於Triton X-100) lyses the cells and also collects cell lysates. If the collected sample is not immediately analyzed by atomic absorption spectroscopy (see below)

Rb+含量，則將其儲存於下，對於後續Rb+分析不會有任 何負面作用。The Rb+ content is stored underneath and will not have any negative effects on subsequent Rb+ analysis.

Rb於上層清液（Rb+Sup)與細胞溶胞產物（Rb'ys)中之濃 度，係在製造者所定義之條件下，使用ICR8000火焰原子吸 收光冶儀（Aurora Biomed 公司，vancouver, b.C.)定量。—份 〇 毫升試樣係經由以等體積之Rb+試樣分析緩衝劑稀釋，及注 入空氣-乙炔火焰中，而自動地自微滴定板處理。於試樣中 之Rb+量係藉由在78〇毫微求下之吸收，使用作為光源之扣 心陰極燈與P则測器進行度量。在試樣分析緩衝劑中： 蓋範圍0-5毫克/升Rb+之校準曲線，係以各組板產生。百分 比Rb+射流（F)係藉由[Rb+ 刀 L Sup/ (Kb Sup+ Rb Lys)] χ 1〇〇0/〇^ 義。 LUVh)/(db)]xlo〇% 定義 化合物之作用⑹係藉由 古其中尽為於化合物存在下’在去極化作用緩衝劑中之射 流’巧為基底緩衝劑中之射流，而&amp;為去極化作用緩衝劑 中之射流，及巧為於化合物存在下，在去極化作用緩衝劑 中之射流。將作用⑹與化合物濃度關係作圖，以計笞％ 值，其係為關於最大Rb+射流之5〇%之化合物濃度^結^ 132252 68- 200914452 係示於下文。說明：A : EC50 = 1 nM - 50 nM ; B : EC50 = 50 nM -100 ηΜ ; C : EC50 = 100 - 200 ηΜ。 表1 舉例化合物之活性The concentration of Rb in the supernatant (Rb+Sup) and cell lysate (Rb'ys) is determined by the manufacturer to use the ICR8000 flame atomic absorption spectrometer (Aurora Biomed, vancouver, bC) ) Quantitative. - Parts liters of the sample are automatically processed from the microtiter plate by dilution with an equal volume of Rb+ sample analysis buffer and injection into an air-acetylene flame. The amount of Rb+ in the sample was measured by absorption at 78 〇 nanometers using a button cathode lamp as a light source and a P detector. In the sample analysis buffer: A calibration curve with a cover range of 0-5 mg/L Rb+ was generated for each set of plates. The percentage Rb+ jet (F) is determined by [Rb+ knife L Sup/ (Kb Sup+ Rb Lys)] χ 1〇〇0/〇^. LUVh)/(db)]xlo〇% defines the role of the compound (6) by using the jet in the depolarizing buffer in the presence of the compound as the jet in the base buffer, and &amp; It is the jet in the depolarizing buffer, and the jet in the depolarizing buffer in the presence of the compound. The effect (6) is plotted against the compound concentration to calculate the % value, which is the concentration of the compound about 5% of the maximum Rb+ jet. ^ 132252 68- 200914452 is shown below. Description: A: EC50 = 1 nM - 50 nM; B: EC50 = 50 nM -100 ηΜ ; C : EC50 = 100 - 200 ηΜ. Table 1 Activity of exemplary compounds

132252 •69-132252 • 69-

Claims (1)

200914452 十、申請專利範圍： 1· 一種式I化合物200914452 X. Patent application scope: 1. A compound of formula I 其中貿與2之至少一個為N;At least one of trade and 2 is N; 其中下文部份基團為基團A或B之一 AThe following group is a group A or B A 有 子 ’其中Ar為1,2-稠合，、員環芳族基團，帶 如下文疋義之取代基心與’且含有零或一個環氮原 BThere is a sub-in which Ar is a 1,2-fused, ring-membered aromatic group, having a substituent core as described below and having a zero or a cyclic nitrogen source B 其中Ar為1,2-稠合六員環芳族基團，帶有如 下文定義之取代基尺1與尺2，且含有零或一個環氮原子； 其中Ri與R2係獨立為Η、CN、鹵素、CH2CN、〇H、N02、 CH2F、CHF2、CF3、CF2CF3、q-Q 烷基、cpoxvQ 烷基、 NH-C! -C6 烷基、NHCPO% -C6 烷基、C(=0)N(CH3 )2、C(=0)N(Et)2 132252 200914452 、（:烧基、CK))0Cl_C6烷基、〇c(=〇)c] _C6烷基、 OCrQ烷基、SCl_C6烷基、〇3七6環烷基、（CH2)mC3_C6環烷 基、c3-cv_t烯基、（CH2)mC3_c6環烯基、C2_q烯基、c2_c6 快基、Ar!、（CHJmAr〗、苯基、吡啶基、吡咯基、（αί2)〆米 唾基、（CH2)』呼基、吱喃基、，塞吩基 ' ㈣)〆号唑基、阳丄 異咢唑基、（CH2 )m噹唑基、（CH2 )m異p塞唑基、（ch2 )m苯基、 (匸吒‘吡咯基、（CH2)n^t啶基或（CH2)m嘧啶基，該環烷基與 δ玄環烯基係視情況含有一或兩個獨立選自〇、N及s之雜 原子，且該烷基、環烷基、環烯基、烯基、炔基、咪唑基、 扯啡基、十坐基、異十坐基”ta坐基、H坐基、苯基、 吡咯基、吡啶基或嘧啶基係視情況被一或兩個基團取代， 取代基獨立選自OH、鹵素、氰基、甲基、乙基或三氣甲 基，其中m為零、！或2 ;或Ri與&amp;和彼等所連接之環碳原 子一起形成5-或6-員稠合環，該環可為飽和、不飽和或芳 族，其係視情況含有一或兩個獨立選自〇、N及s之雜原 子，且其係視情況被鹵素、烷基取代；R，為h、 鹵素CF3或C! -C：3烷基；&amp;與&amp;係獨立為H、CN '鹵素、 cf3 ocf3 oc! -c3烧基或q. c6烧基，所有該Ci _c3烧基與 該Α_(：6烷基視情況被一或兩個基團取代，取代基獨立選 自〇Η、齒素、Cl_C3烷基、〇Ci_C3烷基或三氟甲基； 或S; Υ為〇或s; q = w〇; r^Ci_C6烷基、（酸以3弋 ^ 烷基、（CHR6)WCH2C3-C6 環烷基、CH2(CHR6)wC3_C6 環烷 基、CR6=CH-C3_C6 環烷基、CH=CR6_C3_C6 環烷基: (CHR6)w(VC6環烯基、CH2(CHR6)wc5-c6環烯基、c2_c6烯基、 132252 200914452 c2-c6炔基、ΑΓι、（CHR6)wAri、CH2(CHR6)wAri 或（chr丄呵知 ’其中w = ，Ari為5_至㈣單或雙環狀芳族基團，視 情況含有卜4個獨立選自N、〇及S之環雜原子；R6為氫或 CA烧基；其中全部環院基與環稀基係視情況含有一或兩 個獨立選自N、0及s之環雜原子；其中在Ri，R2，R3，R4，R5Wherein Ar is a 1,2-fused six-membered ring aromatic group having a substituent base 1 and a ruler 2 as defined below, and containing zero or one ring nitrogen atom; wherein Ri and R2 are independently Η, CN , halogen, CH2CN, 〇H, N02, CH2F, CHF2, CF3, CF2CF3, qQ alkyl, cpoxvQ alkyl, NH-C! -C6 alkyl, NHCPO% -C6 alkyl, C(=0)N(CH3 2, C(=0)N(Et)2 132252 200914452, (: alkyl, CK)) 0Cl_C6 alkyl, 〇c(=〇)c] _C6 alkyl, OCrQ alkyl, SCl_C6 alkyl, 〇3 Hexa6-cycloalkyl, (CH2)mC3_C6 cycloalkyl, c3-cv_t alkenyl, (CH2)mC3_c6 cycloalkenyl, C2_q alkenyl, c2_c6 fast radical, Ar!, (CHJmAr, phenyl, pyridyl, pyrrole Base, (αί2) glutinous sulphate, (CH2) 』 s yl, decyl, thiophene ' (4)) oxazolyl, oxime isoxazolyl, (CH 2 ) m oxazolyl, (CH 2 M-iso-p-zozolyl, (ch2)m-phenyl, (匸吒'pyrrolyl, (CH2)n^tidine or (CH2)m-pyrimidinyl, the cycloalkyl and δ-cycloalkenyl-based The case contains one or two heteroatoms independently selected from hydrazine, N and s, and the alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imi Azyl, cyano, decyl, isodecyl, ta, H, phenyl, pyrrolyl, pyridyl or pyrimidinyl are optionally substituted by one or two groups, independently substituted Selected from OH, halogen, cyano, methyl, ethyl or trimethylmethyl, wherein m is zero, ! or 2; or Ri forms a 5- or 6- together with the ring carbon atoms to which they are attached. a fused ring which may be saturated, unsaturated or aromatic, which optionally contains one or two heteroatoms independently selected from the group consisting of hydrazine, N and s, and which are optionally substituted by halogen or alkyl; R, is h, halogen CF3 or C! -C:3 alkyl; &amp;&amp; is independently H, CN 'halogen, cf3 ocf3 oc! -c3 alkyl or q. c6 alkyl, all of this Ci _c3 The alkyl group and the hydrazine _(:6 alkyl group are optionally substituted by one or two groups, the substituents are independently selected from the group consisting of hydrazine, dentate, Cl_C3 alkyl, 〇Ci_C3 alkyl or trifluoromethyl; or S; Is 〇 or s; q = w〇; r^Ci_C6 alkyl, (acid is 3弋^ alkyl, (CHR6)WCH2C3-C6 cycloalkyl, CH2(CHR6)wC3_C6 cycloalkyl, CR6=CH-C3_C6 ring Alkyl, CH=CR6_C3_C6 cycloalkyl: (CHR6)w (VC6 cycloalkenyl, CH2 ( CHR6) wc5-c6 cycloalkenyl, c2_c6 alkenyl, 132252 200914452 c2-c6 alkynyl, ΑΓι, (CHR6) wAri, CH2(CHR6) wAri or (chr丄 knowing 'where w = , Ari is 5_ to (four) a mono- or bicyclic aromatic group, optionally containing four ring heteroatoms independently selected from N, fluorene and S; R6 is hydrogen or a CA alkyl group; wherein all of the ring and ring groups are optionally included One or two ring heteroatoms independently selected from N, 0 and s; wherein in Ri, R2, R3, R4, R5 丨中之全部烷基、環院基、稀基、環稀基、雜環烧 基、雜環烯基、炔基、芳基及雜芳基係視情況被一或兩個 取代基取代，取代基獨立選自Ci_c3院基、由素、〇H 〇Me、 其中全部環烧基與雜環烷 SMe、CN、CH2F及三氟甲基 且 取 基係另外視情況被無論是環外碳-碳雙鍵或羰基取代； 其中烯基與炔基亦另外視情況被苯基或環烷基 代；及其藥學上可接受之鹽。 其中基團All of the alkyl, cyclopentyl, dilute, cycloaliphatic, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl and heteroaryl groups in the oxime are optionally substituted by one or two substituents. The base is independently selected from the group consisting of Ci_c3, 素, 〇H 〇Me, all of the cycloalkyl and heterocycloalkanes SMe, CN, CH2F and trifluoromethyl and the base is additionally taken as the outer carbon-carbon. A double bond or a carbonyl group; wherein the alkenyl group and the alkynyl group are additionally optionally substituted by a phenyl group or a cycloalkyl group; and a pharmaceutically acceptable salt thereof. Group 2.如請求項1之化合物，2. The compound of claim 1, 其係為式IA-1化合物It is a compound of formula IA-1 IA1 132252 200914452 4.如請求項3之化合物，其係為式IA-la化合物IA1 132252 200914452 4. The compound of claim 3 which is a compound of formula IA-la IA-la 5. 如請求項4之化合物，其中R3與R4係獨立為Η、鹵素、曱 基、甲氧基或三氟曱基。 6. 如請求項5之化合物，其中R'與R2係獨立為Η、鹵素、甲 基或三氟曱基。 7. 如請求項6之化合物，其中R5為C3-C6烷基或CH2-C3-C6-環烷 基，且其中R5係視情況被鹵素、羥基或甲氧基取代。 8. 如請求項7之化合物，其中心為Η、F、曱基或三氟曱基。 9. 如請求項8之化合物，其中W與Ζ均為Ν。 10. 如請求項8之化合物，其中W與Ζ之一為Ν，而另一個為C。 11. 如請求項9或10之化合物，其中R3與R4係獨立為Η、曱基 或甲氧基。 12. 如請求項3之化合物，其係為式IA-lb化合物IA-la 5. The compound of claim 4, wherein R3 and R4 are independently oxime, halogen, fluorenyl, methoxy or trifluoromethyl. 6. The compound of claim 5, wherein R' and R2 are independently oxime, halogen, methyl or trifluoromethyl. 7. The compound of claim 6, wherein R5 is C3-C6 alkyl or CH2-C3-C6-cycloalkyl, and wherein R5 is optionally substituted by halogen, hydroxy or methoxy. 8. The compound of claim 7, wherein the center is ruthenium, F, decyl or trifluoromethyl. 9. The compound of claim 8, wherein both W and Ζ are Ν. 10. The compound of claim 8, wherein one of W and Ζ is Ν and the other is C. 11. The compound of claim 9 or 10, wherein R3 and R4 are independently oxime, fluorenyl or methoxy. 12. The compound of claim 3 which is a compound of formula IA-lb 13. 如請求項12之化合物，其中R3與R4係獨立為Η、鹵素、曱 基、曱氧基或三氟曱基。 14. 如請求項13之化合物，其中R/與R2係獨立為Η、鹵素、曱 132252 200914452 基或三氟曱基。 15.^求項14之化合物，其中〜為V或ch2-C3-C6-環 :二且其中化係視情況被南素、羥基或甲氧基取代。 17=項15之化合物，其中…-、甲基或三氣甲基。 w.如衲求項16之化人 $ σ物，其中W與Z均為N。 18.如請求項16之化合 1〇 ^ t 初其中貿與2之一為N，而另一個為C。13. The compound of claim 12, wherein R3 and R4 are independently oxime, halogen, sulfhydryl, decyloxy or trifluoromethyl. 14. The compound of claim 13, wherein R/ and R2 are independently hydrazine, halogen, fluorene 132252 200914452 or trifluoromethyl. 15. The compound of claim 14, wherein ~ is V or ch2-C3-C6-ring: and wherein the chemical system is optionally substituted with a sulphate, a hydroxy group or a methoxy group. 17 = a compound of item 15, wherein ... -, methyl or trimethyl. w. For example, the object of the item 16 is σ, where W and Z are both N. 18. If the combination of claim 16 is 1〇 ^ t one of the trades and one of the two is N, and the other is C. ㈣求項擊之化合物，其中_係獨立㈣、甲基 或甲氧基。 其係為式IA2化合物(4) Compounds that are sought to be hit, in which _ is independent (tetra), methyl or methoxy. It is a compound of formula IA2 IA2 。 2〇·如請求項2之化合物， 21.如請求項20之化合物，其中X為〇，丫為0,且q為〇或卜 月求項21之化合物’其中與R“系獨立為η、鹵素、甲 基、曱氧基或三敦甲基。 23.如凊求項22之化合物，其中R，與〜係獨立為η、鹵素、曱 基或三氟甲基。 士 π月求項23之化合物’其中〜為^々烧基或cH2_C3_c64 烷基，且其中r5係視情況被鹵素、羥基或曱氧基取代。 25. 如請求項24之化合物’其中j^h、f、曱基或三I甲基。 26. 如睛求項25之化合物，其中w與z均為n。 27. 如請求項25之化合物，其中貿與2之一為n，而另一個為c。 28. 如請求項26或27之化合物，其中R^R4*、獨立為H、甲基 132252 200914452 或甲氧基。 29.如請求項2之化合物，其係為式IA3化合物IA2. 2. The compound of claim 2, 21. The compound of claim 20, wherein X is oxime, 丫 is 0, and q is a compound of 〇 or 卜月求21, wherein η is independent of η, Halogen, methyl, decyloxy or triditymethyl. 23. The compound of claim 22, wherein R, and ~ are independently η, halogen, fluorenyl or trifluoromethyl. The compound 'wherein' is a hydrazine group or a cH2_C3_c64 alkyl group, and wherein r5 is optionally substituted by halogen, hydroxy or decyloxy. 25. The compound of claim 24 wherein 'j^h,f, fluorenyl or The compound of claim 25, wherein w and z are both n. 27. The compound of claim 25, wherein one of trade and 2 is n and the other is c. The compound of claim 26 or 27, wherein R^R4*, independently H, methyl 132252 200914452 or methoxy. 29. The compound of claim 2 which is a compound of formula IA3 其中X為〇，γ為〇，且q為〇或1。 30·如請求項29之化合物 31·如請求項30之化合物，其中心與&amp;係獨立為H、鹵素、甲 基、甲氣基或三氟甲基。 32.如請求項31之化合物，其中R，與化係獨立為H、鹵素、甲 基或三氟曱基。 33·如請求項32之化合物，其中化為。'烷基或CH2_C3_q4 烷基，且其中Rs係視情況被鹵素、羥基或甲氧基取代。 34_如請求項33之化合物，其中Ri為Η、F、甲基或三氟甲基。 35·如請求項34之化合物，其中w與Z均為N。 36. 如請求項34之化合物，其中界與乙之一為N，而另一個為c。 37. 如凊求項35或36之化合物，其中R3與心係獨立為Η、甲基 或甲氧基。 38’如印求項2之化合物，其係為式ΙΑ4化合物Where X is 〇, γ is 〇, and q is 〇 or 1. 30. The compound of claim 29. 31. The compound of claim 30, wherein the center and the &quot; are independently H, halogen, methyl, methyl or trifluoromethyl. 32. The compound of claim 31, wherein R, independently of the chemical system, is H, halo, methyl or trifluoromethyl. 33. The compound of claim 32, wherein the compound is converted to. 'Alkyl or CH2_C3_q4 alkyl, and wherein Rs is optionally substituted by halogen, hydroxy or methoxy. 34. The compound of claim 33, wherein Ri is hydrazine, F, methyl or trifluoromethyl. 35. The compound of claim 34, wherein both w and Z are N. 36. The compound of claim 34, wherein one of B and B is N and the other is c. 37. The compound according to item 35 or 36, wherein R3 is independently a cardioline, methyl or methoxy. 38', such as the compound of claim 2, which is a compound of formula ΙΑ4 如請求項38之化合物，其中X為Ο，Υ為〇,且q為〇或1。 132252 200914452 40. 如請求項39之化合物，其中R3與R4係獨立為Η、函素、甲 基、甲氧基或三氟甲基。 41. 如請求項40之化合物’其中R，與化係獨立為Η、_素、甲 基或三氟甲基。 42. 如請求項41之化合物，其中R^C3_c6烧基或cH2_C3_c6_環 院基’且其中r5係視情況被鹵素、經基或甲氧基取代。 43. 如靖求項42之化合物’其中Ri為η、f、曱基或三氟甲基。 44. 如請求項43之化合物，其中〜與2均為Ν。 45. 如凊求項43之化合物，其中w與ζ之一為Ν，而另一個為c。 士明求項44或45之化合物，其中心與係獨立為H、甲基 或曱氧基。 47·如凊求項2之化合物，其係為式IA5化合物The compound of claim 38, wherein X is hydrazine, hydrazine is hydrazine, and q is hydrazine or 1. 132252 200914452 40. The compound of claim 39, wherein R3 and R4 are independently oxime, a functional group, a methyl group, a methoxy group or a trifluoromethyl group. 41. The compound of claim 40, wherein R, independently of the chemical system, is Η, _, methyl or trifluoromethyl. 42. The compound of claim 41, wherein R^C3_c6 alkyl or cH2_C3_c6_cyclyl and wherein r5 is optionally substituted by halogen, thio or methoxy. 43. The compound of claim 42 wherein Ri is η, f, decyl or trifluoromethyl. 44. The compound of claim 43, wherein both ~ and 2 are deuterium. 45. The compound of claim 43, wherein one of w and ζ is Ν and the other is c. The compound of claim 44 or 45, the center of which is independently H, methyl or decyloxy. 47. The compound of claim 2, which is a compound of formula IA5 IA5 。 8.如求項47之化合物，其中X為〇，Y為Ο，且q為0或1。 士 °月求項48之化合物，其中R3與R4係獨立為H、鹵素、甲 基、甲氧基或三氟甲基。 士 Π月求項49之化合物，其中R'與R2係獨立為H、鹵素、甲 基或三氟甲基。 l如β求項50之化合物，其中為C3-C6烷基或CH2-C3-C6-環 土’且其中Rs係視情況被鹵素、羥基或甲氧基取代。 5 2 -^0 士主· 明，項51之化合物，其中Ri為H、F、甲基或三氟曱基。 132252 200914452 . 53·如明求項之化合物，其令w與Z均為N。 54·如凊求項52之化合物，其中W與Z之一為N，而另一個為C。 55.如明求項53或54之化合物，其中心與心係獨立為h、甲基 或甲氧基。 56’種面藥組合物’其包含如請求項1之式I化合物，伴隨著 藥學上可接受之載劑。IA5. 8. The compound of claim 47, wherein X is hydrazine, Y is hydrazine, and q is 0 or 1. The compound of claim 48, wherein R3 and R4 are independently H, halogen, methyl, methoxy or trifluoromethyl. The compound of claim 49, wherein R' and R2 are independently H, halogen, methyl or trifluoromethyl. A compound of the formula 50, wherein is a C3-C6 alkyl group or a CH2-C3-C6-ring ring' and wherein Rs is optionally substituted by halogen, hydroxy or methoxy. 5 2 -^0 士主· Ming, the compound of Item 51, wherein Ri is H, F, methyl or trifluoromethyl. 132252 200914452 . 53. A compound of the formula wherein w and Z are both N. 54. The compound of claim 52, wherein one of W and Z is N and the other is C. 55. The compound of claim 53 or 54, wherein the center and the heart are independently h, methyl or methoxy. A 56&apos; seeding composition&apos; which comprises a compound of formula I as claimed in claim 1 with a pharmaceutically acceptable carrier. 58. —種化合物，其具有以下结構式：58. A compound having the following structural formula: 59. —種化合物，其具有以下、结構式：59. A compound having the following structural formula: 132252.doc 200914452 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：132252.doc 200914452 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 132252132252
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MX2009013581A (en) 2010-01-26
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HRP20120857T1 (en) 2012-11-30
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DK2170861T3 (en) 2012-11-26
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